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International Journal of Molecular Sciences
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20 November 2025

The Significance of the Microenvironment in T/Nk-Cell Neoplasms

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1
Department of Oncology, Medical Faculty Niš, University of Niš, 18000 Niš, Serbia
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Oncology Clinic, University Clinical Center Niš, 18000 Niš, Serbia
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Department of Pathology, Medical Faculty Niš, University of Niš, 18000 Niš, Serbia
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Center of Pathology, University Clinical Center Niš, 18000 Niš, Serbia
Int. J. Mol. Sci.2025, 26(22), 11225;https://doi.org/10.3390/ijms262211225
This article belongs to the Special Issue Study on the Microenvironment in Lymphoma
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Abstract

T/NK-cell neoplasms represent rare and highly diverse cancers, distinguished by variability in their molecular architecture, local inflammatory milieu, and microenvironmental composition, which collectively underpin the diversity of clinical presentations and outcomes. The neoplastic tissue comprises malignant lymphoma/leukemic cells in concert with a spectrum of stromal elements and the acellular extracellular matrix (ECM), collectively constituting the lymphoma microenvironment (LME). These components engage in dynamic, reciprocal interactions, forming a self-regulating ecosystem capable of responding adaptively to both exogenous and endogenous stimuli. Historically, the LME was largely neglected in considerations of lymphomagenesis; however, emerging evidence highlights its pivotal role in driving core oncogenic processes, including sustained proliferative signaling, angiogenesis, immune evasion, and apoptotic resistance. Deciphering the intricate, multidirectional crosstalk among the cellular and acellular constituents of the T/NK-cell neoplastic microenvironment promises to deepen our understanding of disease biology and may inform the development of novel, mechanism-based therapeutic interventions.

1. Introduction

T/NK-cell neoplasms constitute a highly heterogeneous and rare group of cancers [1]. Their presumed cells of origin are mature T or NK-cells. It is hypothesized that oncogenic transformation occurs early in the cellular life cycle, yet the malignant clone retains the capacity for terminal differentiation and maturation. This phenomenon likely reflects preservation of the cellular maturation program, in contrast to immature T/NK-cell counterparts. Although these neoplastic cells are phenotypically mature, they harbor extensive molecular abnormalities, which contribute to the marked histological and clinical heterogeneity observed across distinct entities. Clinically, T/NK-cell neoplasms may present as nodal, extranodal, or leukemic disease, depending on the distribution and growth pattern of the malignant cells, although overlapping patterns are frequently observed.
T/NK-cell neoplasms account for approximately 10–15% of all non-Hodgkin lymphomas (NHL) in adults, classifying them as rare entities [1]. A prominent epidemiological feature of these neoplasms is their association with viral infection, notably Epstein–Barr virus (EBV) and human T-cell lymphotropic virus type 1 (HTLV-1), which underlies marked geographic and racial variation in incidence [1]. The occurrence of T/NK-cell neoplasms closely parallels the prevalence of these viral infections in endemic regions, including the Eastern Hemisphere, with Japan, broader Asia, West Africa, and South America being most heavily affected [2,3].
The two leading international consortia have recently issued updated classifications incorporating the most current advances in the field: the 5th Edition of the World Health Organization Classification of Haematolymphoid Tumors (WHO-HAEM5, 2022) and the International Consensus Classification of Mature T/NK-Cell Neoplasms (ICC, 2022) [4,5,6]. A comparative synthesis of these frameworks is presented in Table 1.
Table 1. T/NK-cell neoplasms/disorders comparative table (WHO 2022 vs. ICC 2022).
Regardless of the classification system employed, a simplified framework commonly categorizes T/NK-cell neoplasms as nodal, extranodal, or leukemic, although overlapping features are frequently observed. Both the WHO-HAEM5 and ICC 2022 have provided integrative approaches to the classification of T/NK-cell neoplasms, incorporating genetics, pathology, immunophenotype, and clinical presentation. A notable advancement in both systems is the unification of nodal T follicular helper (TFH) lymphomas into a single entity and the recognition of EBV+ nodal T/NK-cell lymphoma as a distinct entity [7].
Given their derivation from a common progenitor, T and NK-cell neoplasms are best considered collectively rather than separately. Mature peripheral T-cells are characterized by membrane CD3 expression, reflecting a fully developed T-cell receptor (TCR). Cytotoxic T-cells are further defined by CD8 expression in conjunction with CD3, along with cytoplasmic cytotoxic granules, including perforin, T-cell restricted intracellular antigen (TIA-1), and granzyme B. In the PTCL-NOS subtype, cytotoxic phenotypes are generally associated with more aggressive clinical behavior, although this is not universal [8,9,10,11]. NK-cells, key effectors in innate immunity that also participate in adaptive responses, consistently express CD16, CD57, and CD56. They typically display only the cytoplasmic CD3 ε chain, while membrane CD3 is absent, a hallmark of ENKTCL [12,13,14]. T-helper cells express membrane CD4 alongside CD3, whereas TFH cells are defined by co-expression of biomarkers such as BCL6, CD10, CXCL13, PD-1, SAP, ICOS, and CCR5 [8,15,16]. Aberrant biomarker expression is a central feature of T/NK-cell neoplastic transformation, while EBV-infected neoplastic cells consistently express latent membrane proteins (LMP1/2) and EBV-encoded RNA (EBER).
The LME constitutes a dynamic, interdependent ecosystem comprising non-malignant cellular components, ECM, and a milieu of cytokines, hormones, and exosomes. Within this ecosystem, neoplastic lymphoma cells are intimately intermixed with stromal and acellular elements, forming a unified neoplastic ensemble. The components of the LME engage in complex, reciprocal interactions, providing both supportive and inhibitory signals to malignant cells. Remarkably, the LME functions as an adaptive endogenous ecosystem, capable of harmonizing its activities in response to continuous exogenous and endogenous influences. Historically underappreciated, the LME is now recognized as a critical regulator of core oncogenic processes, including sustained proliferative signaling, angiogenesis, immune evasion, and apoptosis resistance, and is emerging as a compelling focus for translational research. Advances in understanding these interactions are poised to inform the development of targeted therapeutic strategies.

2. The Concept of the Microenvironment in T/NK-Cell Neoplasms

In the classical sense, the LME comprises diverse accessory (non-malignant) cells embedded within acellular matrix components, collectively forming a self-regulating endogenous microecosystem that interacts intimately with malignant lymphoma cells. Functionally, the reactive cellular components, including immune cells, stromal elements, and angiogenic cells associated with the vasculature, together with acellular matrix compounds and the cytokine milieu, establish a complex, dynamic network that modulates signaling pathways, local metabolism, mechanical support, and immune responses, thereby exerting profound influence on lymphoma cell behavior [17]. The LME facilitates malignant cell survival through mechanisms such as sustained proliferative signaling, evasion of growth suppressors, resistance to apoptosis, and immune escape [18]. Figure 1 illustrates the LME as a discrete microenvironmental ensemble composed of its principal cellular and stromal components.
Figure 1. Composition of the lymphoma microenvironment.
Furthermore, the concept of the matrisome, a functional ensemble of genes encoding ECM and ECM-associated proteins, has been introduced to define the coordinated interactions between cellular and acellular stromal components, highlighting the ECM as a living, dynamic microecosystem (Table 2) [19].
Table 2. The matrisome composition.
The heterogeneity in the composition of the LME, determined by the diversity of its cellular constituents and acellular compounds, gives rise to distinct protein transcriptomic topography which serves as a critical determinant of the clinical heterogeneity observed among T/NK-cell neoplasms. Moreover, architectural variability within the LME may exert a profound influence on disease prognosis and outcome.
A substantial subset of T/NK-cell neoplasms is associated with EBV infection, affecting either the neoplastic or the stromal compartment. Such infection may induce transcriptomic perturbations in both cellular groups, culminating in altered antigenic expression and reprogrammed cytokine secretion. These processes contribute to dynamic remodeling of the LME, which may consequently modulate the trajectory of lymphomagenesis in either a facilitative or suppressive manner. Analogous mechanisms are implicated in HTLV-1–associated T/NK-cell neoplasms, particularly in ATLL [20].
Given the pronounced micromorphological diversity of T/NK-cell neoplasms, encompassing differences in morphological appearance, growth architecture, neovascularization patterns, immune checkpoint receptor expression, and stromal cell composition, it is plausible to infer that the LME exhibits both structural and functional heterogeneity across disease subtypes. In this context, delineating the precise LME profiles of individual entities represents an increasingly intricate and challenging endeavor. Ultimately, this complexity may underlie the marked variability in clinical behavior and outcome observed not only across distinct T/NK-cell neoplasms but also among nodal, extranodal, and leukemic counterparts of the same nosological category.
In Table 3, we summarize the principal characteristics of T/NK-cell neoplasms, accompanied by an integrative overview of their corresponding LMEs.
Table 3. T/NK-cell neoplasms/disorders composition overview.

3. Cellular Stroma Composition in T/NK-Cell Neoplasms

The cellular stroma represents a complex assemblage of non-neoplastic cells intimately admixed with malignant lymphoma cells, collectively establishing the characteristic cytoarchitectural organization of T/NK-cell neoplasms. In conjunction with the ECM, the cellular stroma constitutes the LME, a highly dynamic and functionally diverse compartment.
Based on predominant cellular constituents and biological functions, the LME can be broadly delineated into three principal stromal categories: an angiogenic stroma, composed mainly of endothelial cells and pericytes; a classical stromal compartment, encompassing dendritic cells (DCs), lymphoma-associated macrophages (LAMs), mesenchymal stromal cells (MSCs), myeloid-derived suppressor cells (MDSCs), cancer-/lymphoma-associated fibroblasts (CAFs), and mast cells (MCs); and an immune-cellular stroma, characterized by reactive immune elements including T, B, and NK-cells.
The cellular stromal composition varies significantly among T/NK-cell lymphoma subtypes, highlighting that these differences contribute to distinct clinical characteristics and treatment outcomes for each T/NK-cell neoplasm.

3.1. Angiogenic Stroma (Angiogenesis-Neovascularisation)

Angiogenesis is a fundamental process in lymphoma growth and progression. The formation of new blood vessels is driven by pro-angiogenic factors, which are produced by both lymphoma cells and various stromal infiltrating cells, primarily LAMs [21]. In PTCL-NOS, a profile of cytokine expression promotes the polarization of LAMs into M2 macrophages, which stimulate angiogenesis via production of vascular endothelial growth factor (VEGF) and other vasculogenic factors [22]. In fact, in PTCL-NOS, AITL, and ATLL, the majority of the LAMs have been demonstrated to be macrophages with M2 phenotype [23]. T/NK-cell lymphomas with a markedly cellular inflammatory background show more prominent vascular proliferation, which is particularly emphasized in AITL, PTCL, or ENKTCL [24].
The morphologic hallmark of AITL is striking arborized vascularity caused by a CD4+ T follicular helper tumor cell clone in orchestration with a robust microenvironment. The proliferation of high endothelial venules (HEV), follicular dendritic cells, and polymorphous reactive cell infiltrate often obscures the minor tumor cell population, rendering the diagnosis quite challenging [25,26]. Increased expression of VEGF type A, a major angiogenic stimulator, was detected in both the tumor cells and endothelial cells, indicating an active role of microvasculature in AITL progression [27].
PTCL-NOS is characterized by histologically unremarkable moderate angiogenesis; however, high VEGF expression has been linked with poor prognosis [28,29]. The major histologic feature of ENKTCL is angiocentric and angiodestructive growth, together with necrosis. The gene expression profiling study in this aggressive lymphoma revealed alterations in angiogenic pathways and overexpression of VEGF-associated genes [30]. A recent study suggested that silencing of IL-33 inhibited ENKTCL angiogenesis by inactivating the Wnt/β-catenin signaling pathway, and identified IL-33 as a prospective therapeutic target [31].
Studies in B-cell NHL indicated an association with increased microvessel density (MVD) and aggressiveness of the disease [32]. In CTCL, microvascular density was significantly higher compared to normal skin with a benign lymphoid infiltrate, which indicated a possible role of angiogenesis in the development of CTCL [33].
The addition of antiangiogenic agents, including bevacizumab and VEGF inhibitors, to conventional therapeutic strategies has yielded conflicting results in several types of T/NK-cell lymphoma [34,35]. A recent study in a high-grade B-cell lymphoma animal model suggested that the activation of angiogenesis in lymphomas differs significantly from that in solid tumors [36]. It was found that non-canonical signaling pathways exerted via VEGFR-3 and LTβ-receptor drive a distinct morphogenic pattern of vasculature formation, while classic, major signaling pathways (HIF-1α or Notch) are not activated. This may have profound implications for anti-angiogenic therapy in lymphoma and certainly warrants further studies.

3.2. Stromal Cells

DCs are professional antigen-presenting cells (APCs) that bridge innate and adaptive immunity by recognizing tumor or viral antigens and activating naïve CD8+ and CD4+ T-cells [37]. In ENKTCL, DCs are exposed to tumor, and EBV-derived immunosuppressive factors, acquiring a tolerogenic phenotype that impairs antigen presentation and weakens T-cell priming, enabling immune evasion and tumor progression [38]. The absence of immune pressure accelerates tumor proliferation and the accumulation of additional oncogenic alterations.
Within the ENKTCL microenvironment, cytokines such as IL-10, TGF-β, and PGE2 inhibit DC maturation, maintaining them in an immature state that promotes immune tolerance rather than activation [39,40,41]. Tolerogenic DCs secrete IL-10, TGF-β, and indoleamine 2,3-dioxygenase (IDO), leading to tryptophan depletion, T-cell arrest, Treg expansion, and apoptosis, creating a profoundly immunosuppressive niche [42,43,44]. Tumor-derived and EBV-associated factors (e.g., LMP1) further downregulate MHC I/II and co-stimulatory molecules CD80/CD86, preventing effective T-cell priming [37,45].
Functionally, ENKTCL-associated DCs fail to secrete cytotoxic lymphocyte-recruiting chemokines (CXCL9, CXCL10, CCL5) and may instead attract Tregs or MDSCs, resulting in reduced CD8+ T-cell and NK-cell infiltration, an “immune-cold” phenotype resistant to checkpoint blockade [46,47,48].
Therapeutically, reversing DC dysfunction through vaccines, TLR agonists, FLT3 ligands, or combination with immune checkpoint inhibitors may enhance antitumor immunity and improve treatment efficacy in ENKTCL.
LAMs are myeloid-lineage cells derived from circulating monocytes, which are recruited into the LME by tumor, and EBV-derived factors such as CCL2, colony-stimulating factor 1 (CSF-1), and inflammatory cytokines [21,49]. Within the LME, LAMs predominantly adopt an M2-like (alternatively activated) phenotype, expressing markers such as CD163, CD206, and arginase-1, and producing anti-inflammatory cytokines including IL-10 and TGF-β [50,51,52]. This polarization is further reinforced by hypoxia, metabolic stress, and signals from malignant T/NK-cells [50]. M2-type LAMs promote angiogenesis, lymphangiogenesis, tissue remodeling, and tumor cell proliferation, while suppressing adaptive immune responses, contributing to drug resistance, aggressive histology, and poor clinical outcomes [21,53,54].
A key immunosuppressive mechanism of LAMs involves the induction and maintenance of regulatory T-cells (Tregs). IL-10 inhibits effector T-cell activation and proliferation and promotes the differentiation of naïve CD4+ T-cells into inducible Tregs, while TGF-β drives FOXP3 expression and stabilizes Treg suppressive function. LAMs also express indoleamine 2,3-dioxygenase (IDO), which depletes tryptophan and generates kynurenine metabolites, arresting T-cell proliferation, inducing apoptosis, and further promoting Treg expansion. In addition, chemokines such as CCL17 and CCL22 selectively recruit Tregs via CCR4, creating a profoundly immunosuppressive niche that inhibits CD8+ cytotoxic T-cells and NK-cells and facilitates immune escape [55].
In EBV-driven neoplasms such as ENKTCL, LAMs not only secrete immunosuppressive cytokines but also express PD-L1, induced by EBV-mediated oncogenic signaling (e.g., LMP1) and inflammatory mediators such as IL-10 and IFN-γ [56]. PD-L1+ macrophages reinforce T-cell dysfunction and contribute to resistance to PD-1/PD-L1 checkpoint blockade [57]. Beyond immunosuppression, LAMs promote tumor growth through secretion of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), supporting angiogenesis, extracellular matrix remodeling, and recruitment of additional stromal elements [53,54].
Clinically, high densities of CD68+ or CD163+ LAMs in the LME are strongly associated with poor progression-free survival (PFS) and overall survival (OS) in patients with mature T/NK-cell lymphomas [58,59]. T/NK-cell neoplasms are typically characterized by hyperinflammatory stroma with hyperactive macrophages. The characteristic cytokine spectrum of M2-type macrophages is high expression of IL-10 and low expression of IL-12. Increased LAM infiltration correlates with B symptoms, extranodal involvement, chemoresistance, and impaired response to immunotherapy [60]. In PTCL-NOS, malignant T-cells drive LAM proliferation via the JAK/CSF1R signaling axis, and experimental dual inhibition of these pathways reduces macrophage expansion, decreases disease burden, and prolongs survival in preclinical models [61].
Taken together, LAMs represent central regulators of the LME in T/NK-cell lymphomas, integrating tumor-promoting, immunosuppressive, and stromal-supportive functions. Therapeutic strategies targeting LAM-mediated mechanisms, including cytokine blockade (IL-10, TGF-β), metabolic inhibition (IDO), PD-L1 blockade, and disruption of JAK/CSF1R-driven proliferation offer promising avenues to restore antitumor immunity, enhance the efficacy of immunotherapies, and improve clinical outcomes in these aggressive malignancies.
The MSCs are multipotent cells found in various tissues, including bone marrow, adipose tissue, and the stroma of lymphoid organs and could exhibit both anti-inflammatory, and immunosuppressive properties [49,62]. MSCs within the ENKTCL microenvironment can inhibit anti-tumor immune responses through multiple mechanisms. They secrete immunosuppressive cytokines such as IL-10, TGF-β and PGE2, which impair DCs maturation, reduce cytotoxic T lymphocyte and NK-cell function, and promote Treg expansion [63]. These factors create an immunosuppressive milieu that enables EBV-infected NK/T-cells to evade immune surveillance. Furthermore, MSCs may express or induce the expression of immune checkpoint ligands, including PD-L1, on themselves or on other immune and stromal cells, thereby contributing to T-cell exhaustion, and resistance to immune checkpoint inhibitors [63].
ENKTCL-derived or tumor-educated MSCs can produce a range of growth factors and extracellular matrix components that facilitate tumor cell proliferation, invasion and survival, such as VEGF, hepatocyte growth factor (HGF) and stromal-derived factor 1 (SDF-1/CXCL12). The interaction between MSCs and malignant lymphoma cells may also involve exosome-mediated communication, in which MSC-derived exosomes carry microRNAs, cytokines, and other molecules that alter gene expression and promote tumor progression [64]. MSCs have been implicated in the development of chemoresistance in various hematological malignancies, including lymphoma. In ENKTCL, MSCs may protect tumor cells from apoptosis by secreting soluble anti-apoptotic factors (e.g., IL-6, CXCL12), altering drug metabolism in the LME and physically shielding tumor cells through the formation of protective stromal niches [65,66]. These mechanisms reduce the efficacy of cytotoxic agents and contribute to the refractory nature of ENKTCL.
Tumor cells and the inflammatory microenvironment can actively recruit MSCs from bone marrow or surrounding tissues. This recruitment is mediated by chemokines such as CCL2, CXCL8 and CXCL12, as well as factors secreted by EBV-infected cells [67]. Once in the LME, MSCs may differentiate into CAFs or other supportive stromal phenotypes that further enhance tumor growth, and immune escape [68].
In ENKTCL, mesenchymal stromal cells are key contributors to the establishment and maintenance of an immunosuppressive and tumor-supportive microenvironment. Through cytokine secretion, immune modulation, metabolic support, and physical interactions with tumor cells, MSCs help drive disease progression, immune evasion, and treatment resistance [69]. Targeting MSC-tumor interactions or reprogramming stromal cell functions may offer new therapeutic avenues to improve outcomes in this aggressive lymphoma.
MDSCs are a heterogeneous population of immature myeloid cells that expand under pathological conditions such as cancer, chronic infection, and inflammation, and possess potent immunosuppressive activity [70]. In ENKTCL, MDSCs are recruited and activated within the tumor microenvironment (TME) by EBV- and tumor-driven factors, including GM-CSF, IL-6, TGF-β, CCL2, and CXCL8, which promote both monocytic (M-MDSC) and granulocytic (PMN-MDSC) subtypes and enhance their suppressive phenotype [71,72,73].
MDSCs inhibit antitumor immunity through multiple mechanisms. Arginase-1 (ARG1) depletes extracellular L-arginine, downregulating the CD3ζ chain of T-cell receptors and arresting T-cell proliferation [74,75,76]. Inducible nitric oxide synthase (iNOS) produces nitric oxide, disrupting TCR signaling and inducing T-cell apoptosis [77]. IDO degrades tryptophan into kynurenine, suppressing T-cell responses and promoting Treg differentiation [72,78]. Additionally, reactive oxygen species (ROS) generated by MDSCs induce oxidative stress in CD8+ T-cells and NK-cells, impairing cytotoxic function [79]. MDSC-derived IL-10 and TGF-β further suppress dendritic cell maturation, reduce pro-inflammatory cytokine production, and expand FOXP3+ Tregs, reinforcing immunosuppressive networks within the LME [80,81].
CAFs, although primarily studied in solid tumors and B-cell lymphomas, are increasingly recognized in T/NK-cell neoplasms as modulators of the microenvironment. CAFs remodel the ECM, secrete IL-6, CXCL12, and TGF-β, and cooperate with malignant cells to establish pro-inflammatory and immunosuppressive niches, intersecting with key pathways such as JAK/STAT and NF-κB and enhancing immune evasion via PD-L1 upregulation [82,83,84,85].
Although direct functional data for T/NK-cell neoplasms are limited, the EBV-driven cytokine milieu, characterized by IL-6 and IL-10, likely amplifies CAF-like mechanisms, linking stromal remodeling, inflammation, and immune suppression. WHO-HAEM5 formally recognizes stroma-derived neoplasms, underscoring the clinical and biological relevance of fibroblastic elements in lymphoid malignancies [4]. Collectively, MDSCs and CAFs represent central stromal hubs where immune escape, inflammation, and tissue remodeling converge, highlighting potential therapeutic targets in T/NK-cell lymphomas [82].
MCs are clearly significant in certain T/NK-cell lymphomas (especially AITL, CTCL) where they help drive inflammation, angiogenesis, Th17 cell presence, and worse disease behavior. For NK/T-cell lymphomas specifically, there is little direct evidence so far for mast cell involvement, so this is an open area. MCs actively contribute to angiogenesis and induce neovascularization by releasing the classical proangiogenic factors including VEGF, FGF-2, PDGF, and IL-6, and nonclassical proangiogenic factors mainly proteases including tryptase and chymase. MCs support tumor invasiveness by releasing a broad range of matrix MMPs [86].

3.3. Immuno-Cellular Stroma (Reactive T, NK and B Lymphocytes)

The LME of T/NK-cell lymphomas comprises reactive immune cells: CD8+ cytotoxic T-cells, Tregs, reactive NK-cells, TFH, and CD4+ helper T-cells, forming the immune-cellular stroma. Malignant tissue mainly consists of neoplastic T/NK-cells, while data on reactive counterparts remain scarce. Immune subtyping divides these neoplasms into “inflamed” and “immune-suppressed” categories, with T-cell exhaustion linked to poor outcomes [87,88].
Reactive CD8+ T-cells exhibit antitumor activity mainly in early disease, whereas Th2 polarization suppresses cytotoxicity via IL-4, IL-5, and IL-13, and reduced IFN-γ/IL-12 [89]. High CD8+ T-cell counts correlate with better prognosis in some CTCLs.
Tregs foster immunosuppression by secreting IL-10, IL-35, TGF-β, expressing PD-1, CTLA-4, LAG-3, and depleting IL-2 [90]. They suppress multiple immune subsets. Wang et al. identified four Treg subsets, suppressor, tumor-killing, malignant, and incompetent, with their proportions influencing prognosis; e.g., in AITL, incompetent or tumor-killing Tregs correlate with better outcomes [91].
TFH cells, expressing CXCL13, PD-1, ICOS, and BCL6, are diagnostic for AITL and related PTCL-NOS variants [92]. The roles of TFH and CD4+ helper cells remain unclear.
Reactive NK-cells, difficult to distinguish from malignant counterparts, can be evaluated by KIR repertoire diversity (polyclonal = reactive) [93,94]. In T/NK neoplasms, reactive NK-cells often exhibit functional exhaustion, sometimes EBV-infected, losing cytotoxic capacity [93,94,95].
Among T/NK-cell neoplasms, ENKTCL is best characterized. It displays high stromal heterogeneity shaped by EBV, which enhances PD-L1 expression and alters cytokine/chemokine signaling [57]. T and NK-cells show exhaustion (PD-1, TIM-3, LAG-3 expression) and are functionally depleted. Malignant NK-cells secrete dipeptidyl peptidase-4 (DPP4), suppressing chemotaxis of normal NK/T-cells and eosinophils; DPP4 inhibition may restore Th1 activity and synergize with PD-1 blockade [96].
Antigen presentation is impaired by defective DC maturation and PD-L1–high DCs, promoting T-cell anergy [97]. JAK3/STAT3 mutations further induce PD-L1, reinforcing immune evasion [38,88]. Immune checkpoint inhibitors show durable but limited efficacy in ENKTCL [98,99,100]; combining them with DPP4 or JAK inhibitors or adoptive T-cell therapy may improve outcomes.
Bystander B-cells represent non-malignant (reactive) B lymphocytes residing within the LME of T/NK-cell lymphomas. These cells are frequently infected by EBV, facilitating complex interactions with neoplastic lymphoma cells and other immune constituents. Through these interactions, bystander B-cells may modulate the biological behavior of the malignancy, influencing both disease progression and therapeutic responsiveness, although their precise functional role remains to be fully elucidated [101]. It has been demonstrated that reactive B-cells secrete anti-inflammatory cytokines, including IL-10 and TGF-β, thereby fostering a pro-tumorigenic microenvironment via suppression of T-cell–mediated immune responses [102].
Among T-cell lymphomas, AITL constitutes a prototypic example characterized by a distinctive microarchitectural organization enriched with scattered EBV+ bystander B-cells within a reactive background. This histopathological feature is associated with a propensity toward secondary aggressive B-cell lymphomagenesis, particularly diffuse large B-cell lymphoma (DLBCL), during the clinical course of long-standing AITL [103]. Analogous observations have been reported in peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), in which the presence of EBV+ bystander B-cells correlates with similar disease evolution culminating in DLBCL transformation [104].
In the context of CTCL, infiltration by reactive B-cells appears to exert a biologically relevant impact, demonstrating significant associations with advanced disease stages and reduced PFS [105]. In contrast, within ENKTCL, a high density of bystander B-cell infiltration has been paradoxically linked to favorable clinical outcomes, including improved OS, observed in approximately 40% of affected patients [106].

4. Acellular Stroma-Extracellular Matrix Composition in T/NK-Cell Neoplasms

The acellular stroma comprises amorphous substances and protein fibers secreted by stromal (accessory) cells in concert with lymphoma cells, together forming the ECM. Figure 1 has illustrated the composition of the ECM in earlier section. In this context, the terms acellular stroma and ECM are largely synonymous. The amorphous component consists primarily of glycoproteins and proteoglycan complexes, while collagen and elastin fibers provide structural support, creating a three-dimensional scaffold. Incorporation of functionally active biomolecules—including remodeling enzymes and their inhibitors, cytokines, hormones, exosomes, and other mediators—completes the fully functional ECM architecture.
The ECM represents a complex, dynamic, and interactive medium in which stromal and lymphoma cells form an inseparable ensemble essential for tissue homeostasis. It provides structural support and regulates cell behavior through biochemical and mechanical cues, mainly via interactions with integrins [107]. Acting as a reservoir for bioactive molecules, the ECM releases growth factors and cytokines upon disruption, influencing the local microenvironment [108].
Tissue development depends on the ECM’s control of proliferation, migration, differentiation, and apoptosis [107]. Its major structural proteins, collagens and elastin, ensure tensile strength and elasticity. Collagen, comprising about 30% of total body protein, includes at least 28 subtypes, while elastin maintains tissue extensibility [109].
Glycoproteins—such as fibronectin, laminin, tenascin, and thrombospondin—mediate adhesion, migration, and signaling between cells and the ECM. Fibronectin provides scaffolding for ECM assembly; laminin stabilizes basement membranes; and tenascins and thrombospondin modulate adhesion and cell–matrix interactions [110,111].
Proteoglycans consist of core proteins linked to glycosaminoglycan (GAG) chains that confer compressive resistance and interact with growth factors. Large proteoglycans include aggrecan and versican, while small leucine-rich proteoglycans (decorin, biglycan, fibromodulin, lumican) regulate tissue integrity and ECM organization.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that remodel the ECM in physiological and pathological contexts [112,113]. They release growth and angiogenic factors, cleave receptors, and modulate cytokines [114,115]. Their activity is controlled by tissue inhibitors of metalloproteinases (TIMPs), which also have MMP-independent roles in proliferation and apoptosis. Dysregulation of the MMP–TIMP balance may drive excessive ECM degradation, offering potential therapeutic targets [109].
Altogether, ECM components critically shape the LME and influence the lymphomagenesis of T/NK-cell neoplasms, emphasizing the need to clarify their individual and collective functions.

4.1. Role of Extracellular Matrix Protein Fibers in T/NK-Cell Lymphomagenesis

Data on the precise role of collagens and other ECM fibers in the pathogenesis of T/NK-cell neoplasms remain limited. Most available evidence derives from studies across diverse malignancies rather than T/NK-cell lymphomas specifically. In general, tumor-specific ECM is characterized by increased collagen density, resulting in greater tissue stiffness, which has been correlated with poor prognosis in multiple cancer types, although the mechanistic basis for this association remains incompletely understood. Notably, enhanced collagen fibrosis is infrequently observed in T/NK-cell neoplasms, with the possible exception of ENKTCL.
Studies suggest that collagen may facilitate cancer cell proliferation and migration while simultaneously modulating the function and phenotype of tumor-infiltrating immune cells, including lymphoma-associated macrophages (LAMs) and T-cells. This indicates that tumor-associated collagen may exert immune-regulatory effects within the tumor microenvironment, influencing both disease progression and responsiveness to immunotherapy. The ability of the ECM to shape immune cell behavior has given rise to the emerging field of matrix immunology.
Current evidence largely focuses on type I collagen, the most abundant collagen isoform, though other collagen types may exert distinct effects on immune cells [116]. Both transmembrane and extracellular collagens produced by tumor and stromal cells can engage leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1, CD305), activating inhibitory signaling pathways. Overexpression of collagen type XVII on target cells has been shown to reduce NK-cell cytotoxicity. Collectively, these findings suggest that tumor-expressed collagens contribute to immune evasion by directly modulating T and NK-cell activity or indirectly affecting other microenvironmental components such as macrophages [117].
Excessive collagen deposition contributes to ECM stiffness, which may enhance tissue fibrosis and impair drug delivery to lymphoma cells [118]. In ENKTCL, fibrosis can promote necrosis and angio-destructive processes, occasionally leading to pseudo-epithelial hyperplasia—a characteristic histopathologic feature—and may contribute to treatment resistance [119,120]. Collagen can also impede NK-cell-mediated cytotoxicity by promoting a shift toward cytokine production and by facilitating the formation of a protective glycocalyx on cancer cells, further enabling immune evasion. Moreover, cancer cells can remodel collagen to reinforce tumor progression, enhancing adhesion and migration. Consequently, targeting collagen deposition in the tumor microenvironment may augment NK-cell cytotoxicity and represent a potential therapeutic strategy. Clinically, the density and composition of collagen within tumors often correlate with prognosis, with higher collagen levels generally indicating poorer outcomes.
The role of elastin fibers in T/NK-cell lymphomagenesis has not been systematically investigated. Available data pertain primarily to ENKTCL, where lymphoma cells exhibit angiocentric growth patterns that disrupt and destroy elastic fibers within blood vessel walls. This process, accompanied by fibrinoid deposition and ischemia, contributes to the characteristic necrosis observed histologically. Widespread infiltration of lymphoma cells into the elastic lamina of small arteries further defines the distinctive histopathologic landscape of ENKTCL [121].

4.2. Role of Extracellular Matrix Glycoproteins in T/NK-Cell Lymphomagenesis

Glycoproteins are among the most dysregulated components of the cancer matrisome. Certain glycoproteins are consistently up or downregulated across multiple malignancies compared with normal tissues, suggesting their involvement in general mechanisms of tumor progression [19].
Fibronectin, for instance, exhibits altered expression in T/NK-cell neoplasms as well as in other cancers, promoting tumor growth, migration, invasion, and resistance to therapy [122]. Within the lymphoid system, fibronectin is typically absent in healthy lymph nodes but is overexpressed in neovasculature associated with tumors, including lymphomas. Notably, the extra domain B (ED-B) isoform is frequently localized to the lymphoma-associated subendothelial ECM and serves as a recognized angiogenic marker. Overexpression of ED-B fibronectin has been documented across various lymphoma types, representing a potential therapeutic target. In a xenograft model of B-cell NHL, Schliemann et al. demonstrated that a fusion protein, L19-IL2, in combination with rituximab, could achieve complete eradication of lymphoma cells [123]. Accordingly, ED-B fibronectin constitutes a promising target for monoclonal antibody-based therapies aimed at both visualization and treatment of lymphomas. In T/NK-cell neoplasms, fibronectin contributes to tumor aggressiveness and survival by modulating the microenvironment, facilitating cell adhesion, migration, and resistance to therapy [122]. While direct targeting of fibronectin is not yet standard practice, disruption of fibronectin–integrin interactions may represent a viable translational approach to compromise the survival niche of T/NK lymphoma cells.
Data on laminin involvement in T/NK-cell lymphomagenesis are limited. Gene expression analyses (e.g., LAMB2, LAMC2) suggest potential roles in the T-cell lymphoma microenvironment, and ECM studies confirm its presence, albeit to a lesser extent relative to other matrix proteins. Laminin isoforms are established modulators of T-cell behavior within lymphoid tissues and may indirectly influence lymphoma biology. Some evidence indicates laminin can inhibit NK-cell-mediated tumor cytotoxicity through interactions with both NK cells and tumor cells, while other studies suggest NK cells can produce laminin, contributing to regulation of tumor invasion [124]. The oncofetal antigen immature laminin receptor protein (OFA-iLRP) is highly conserved, expressed in fetal tissues and various cancers, including hematopoietic malignancies, but absent in physiologically differentiated adult cells. OFA-iLRP represents a potential target for T-cell-based immunotherapy in hematologic malignancies [125]. Similarly, the laminin receptor (LR) is overexpressed in neoplastic cells relative to normal counterparts and may serve as a biomarker of metastatic aggressiveness across multiple cancers, including leukemia and lymphoma [126].
Tenascin-C is overexpressed in both embryonic and adult ECM, particularly in tumor tissues [127,128]. Its expression correlates spatially and temporally with tumor neovascularization and may confer anti-adhesive and immunosuppressive properties, thereby promoting lymphoma cell survival, migration, and angiogenesis [129,130,131,132]. In a study using the monoclonal antibody tenatumomab across 100 patients with T/NK-cell neoplasms (75 PTCL; 25 CTCL), tenascin-C expression was observed in multiple subtypes, including ALCL, ALK-negative (n = 21), ALCL, ALK-positive (n = 19), PTCL-NOS (n = 20), MF (n = 13), AITL (n = 9), CD30+ primary CTCL (n = 6), and other subtypes (n = 12). While expression intensity varied, no statistically significant differences were observed (p = 0.334). A high proportion of tenascin-C expression (>50%) was noted in ALCL, ALK− (81%), AITL (78%), and ALCL, ALK+ (58%), whereas PTCL-NOS (30%) and CTCL (24%) showed lower expression (p = 0.0019). Gene expression datasets confirmed significant tenascin-C overexpression in T/NK-cell neoplasms compared to normal tissues [128]. Histologic subtypes such as ALCL and AITL exhibited strong, diffuse tenascin-C staining, whereas MF/SSy and primary cutaneous ALCL displayed less intense, sparse staining. These differences likely reflect tissue remodeling and neoangiogenesis characteristic of aggressive PTCL. Notably, vascular-associated tenascin-C expression may influence survival outcomes, highlighting its potential as a therapeutic target, as evidenced by the activity of radiolabeled tenatumomab [133,134].

4.3. Role of Proteoglycans in T/NK-Cell Lymphomagenesis

Proteoglycans are key effectors within the pericellular zone in both healthy and malignant tissues. In lymphoid malignancies, increased mRNA and protein expression of serglycin has been detected in malignant cells, suggesting that proteoglycan synthesis accompanies lymphoid transformation [135]. Syndecan-4 is overexpressed in malignant T cells from patients with SSy, implicating it in disease pathogenesis and representing a potential therapeutic target [136]. Similarly, aberrant upregulation of versican isoform V1 by Sézary cells has been associated with enhanced migration and cutaneous tropism, while potentially sensitizing cells to chemotherapeutics [137,138].
Proteoglycans exhibit context-dependent effects in cancer progression and metastasis. Certain proteoglycans, such as syndecan-1 and glypican-1, promote tumor growth and dissemination by enhancing growth factor signaling and cell migration, whereas others, including decorin and lumican, inhibit tumor progression by modulating immune responses and collagen fibrillogenesis. Collectively, proteoglycans contribute to the regulation of microenvironmental inflammation and immunity, influencing both lymphoma biology and therapeutic responses [139].

4.4. Role of MMPs and TIMPs in T/NK-Cell Lymphomagenesis

Dysregulated activity of matrix metalloproteinases (MMPs) has been recognized as a key contributor to cancer dissemination by degrading the ECM components and facilitating cellular migration. Both MMPs and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), play critical roles in the development and progression of various lymphomas. Specifically, MMP-2 and MMP-9 are central to ECM remodeling across multiple lymphoma subtypes. Elevated expression and activation of these enzymes are associated with tumor invasion, metastasis, and poor clinical outcomes. Mechanistically, MMP overexpression may be induced by interactions with endothelial cells, accelerating lymphoma progression.
Among T/NK-cell neoplasms, evidence indicates that MMP dysregulation significantly impacts disease behavior in select entities. MMP-9 overexpression is particularly characteristic of ENKTCL, where it degrades multiple ECM substrates—including fibronectin, laminin, collagen, elastin, and casein—contributing to the tumor’s high propensity for dissemination and the extensive necrosis commonly observed [140,141]. ENKTCL is typified by vascular invasion and ECM destruction; elevated MMP-9 may exacerbate tissue necrosis via enhanced angiodestruction and may contribute to chemoresistance by impairing drug delivery [140,142]. Additional proteolytic activity by MMP-1 and MMP-11 may be linked to EBV-driven mechanisms. High expression levels of MMP-26 and MMP-9 have also been associated with disease invasiveness and progression, and these enzymes may serve as biomarkers to distinguish ENKTCL from reactive lymphoid hyperplasia, highlighting their potential prognostic value [143].
In contrast, expression of MMP-2 and MMP-9 in other lymphoma subtypes appears less pronounced than in epithelial malignancies, likely reflecting differences in stromal composition; fibroblasts dominate ECM remodeling in carcinomas, whereas lymphoid stroma is more cellularly heterogeneous. Synthetic agents that modulate TIMP activity or inhibit cytotoxic granule secretion have been proposed as therapeutic alternatives, though the dual and context-dependent functions of TIMPs have limited their clinical utility to date [144].
Dysregulated ECM contributes to lymphoma progression through both direct and indirect mechanisms. Directly, ECM alterations influence malignant cell transformation, expansion of cancer stem cells, and disruption of tissue polarity, facilitating invasion and metastasis. Indirectly, ECM remodeling affects stromal cells, promotes angiogenesis and inflammation, and establishes a tumor-permissive microenvironment [145,146,147]. In lymphomas, ECM dysregulation is characterized by vascular disorganization, enlarged vessel pores driven by VEGF, PDGF-β, and TGF-β overexposure, hypoxia, and impaired systemic immune cell infiltration. Locally, immune cells secrete pro-proliferative cytokines: M2-polarized macrophages produce IL-10, TFH cells secrete IL-21, and Th17 and CD8+ T-cells produce IL-6, collectively supporting lymphoma cell survival and invasion.
Despite the limited success of early-phase clinical trials with broad-spectrum MMP inhibitors, dysregulated MMP activity—particularly in early disease stages—remains an area of active investigation. Future therapeutic strategies are likely to focus on the selective inhibition of individual MMP family members to mitigate off-target effects and improve clinical outcomes [148].

4.5. Role of Cytokines, Cytokine Receptors, Growth Factors in T/NK-Cell Lymphomagenesis

Cytokines constitute pivotal intercellular mediators that orchestrate communication among the diverse cellular constituents of lymphomas. Their expression patterns are highly heterogeneous and frequently correspond to specific T/NK-cell neoplasm subtypes. Intriguingly, such heterogeneity may also manifest within tumors of identical histological classification. Functionally, cytokines critically influence the inflammatory microenvironment, a topic that will be elaborated in the dedicated section on inflammation. Among these, most notably IL-6 play a central role in establishing and maintaining an inflammatory milieu that supports lymphoma cell survival and progression.

4.6. Role of Exosome or Lymphoma Cell Extracellular Vesicles in T/NK-Cell Lymphomagenesis

Lymphoma cell–derived extracellular vesicles (LCEVs) have been assigned a multifaceted role in the regulation of lymphoma homeostasis. Structurally, similar to other exosomes, LCEVs possess a bilayer lipid membrane enriched with surface-targeting molecules such as tetraspanins (CD9, CD63, and CD81), major histocompatibility complex (MHC) class I and II proteins, and integrins. Their internal cargo includes various nucleic acids, DNA harboring fusion genes (e.g., EML4-ALK), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), as well as proteins such as soluble NSF attachment protein receptor (SNARE), annexin, flotillin, ALG-2–interacting protein X (Alix), tumor susceptibility gene 101 (TSG101), and mutated variants including mutMYD88 [149,150,151].
Historically, exosomes were regarded as cellular waste products released into the ECM. However, current evidence attributes to LCEVs a broad modulatory function within the LME, where they influence immune evasion, therapeutic response, and drug resistance, and may also serve as novel “multi-omic vesicles” for disease detection [152]. Increasing attention has been directed toward LCEV-mediated interactions between malignant cells, immune cells, and other LME constituents as pivotal drivers of lymphoma progression and treatment outcomes [153].
In EBV+ NK-cell lymphoproliferative disorders (LPDs), it has been proposed that EBV+ memory B-cells continuously secrete exosomes that potentiate the immunosuppressive effects of infected cells, promote clonal proliferation of EBV+ T/NK-cells to variable extents, and thereby contribute to the heterogeneous clinical course and prognosis of these entities [154]. Cumulative evidence indicates that lymphoma-derived exosomes critically contribute to lymphomagenesis, disease progression, and treatment resistance [155,156,157]. Among the best-characterized immune evasion pathways, the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis plays a central role [158]. Elevated levels of circulating and membrane-bound PD-L1 have been identified as adverse prognostic indicators and potential diagnostic and prognostic biomarkers in ENKTCL [159].
In summary, the extensive release of exosomes by lymphoma and immune cells represents a key mechanism in sustaining lymphoma progression and shaping the immunoregulatory landscape of the LME.

5. Role of the Biological Agencies (EBV and HTLV-1) in T/NK-Cell Lymphomagenesis

It has long been established that EBV primarily infects B lymphocytes as well as various stromal components surrounding neoplastic T or NK-cells. More recent evidence, however, has demonstrated that EBV is also capable of directly infecting T and NK-cells themselves. This phenomenon contributes to the molecular reprogramming of these cells within the context of the surrounding LME, thereby influencing lymphoma pathobiology. In parallel, HTLV-1 exhibits a distinct CD4+ T-cell tropism, leading to direct infection of these lymphocytes. The resultant molecular alterations closely parallel those observed in EBV-mediated transformation, highlighting convergent mechanisms of virus-driven lymphomagenesis.

5.1. EBV as the T/NK-Cell Lymphoma Promoting Agent

EBV is nearly ubiquitous, with serologic evidence of prior infection detected in more than 90% of adults worldwide. Despite this widespread exposure, the incidence of T/NK-cell lymphomas remains low, indicating that EBV infection alone is insufficient to induce malignant transformation. Rather, EBV likely acts as an initiating event that increases susceptibility to oncogenesis in a permissive host environment.
The significantly higher prevalence of T/NK-cell malignancies in EBV-endemic regions further supports the contribution of additional cofactors. The interplay between extrinsic (environmental) and intrinsic (genetic) determinants appears critical in driving tumorigenesis, reinforcing the concept of cancer as a multifactorial disease process.
Histologic and molecular analyses of paraffin-embedded tumor specimens have strengthened the evidence for a viral role in oncogenesis. Detection of EBER transcripts by ISH remains a diagnostic hallmark for identifying EBV-associated T/NK-cell neoplasms. Cumulative molecular data now support EBV as an early oncogenic driver in a subset of nodal, extranodal, and leukemic T/NK-cell entities. Moreover, EBV genome sequencing has revealed two major viral strains and several variants of the LMP1, each exhibiting distinct oncogenic potentials that may contribute to the biological and clinical heterogeneity of these lymphomas [2].
EBV displays a strong tropism for B-cells and epithelial cells, with the complement receptor 2 (CD21) serving as the principal entry receptor. However, the mechanism by which T-cells and NK-cells become infected has long remained unclear. One proposed explanation is that EBV infects common lymphoid progenitor cells expressing CD21, which subsequently differentiate into NK-cell and T-cell lineages. This hypothesis provides a plausible basis for the presence of EBV within non–B-cell compartments and may account for the clonal EBV genomes observed in EBV-associated T/NK-cell lymphomas. Nevertheless, recent findings have demonstrated that the type 2 EBV strain possesses a unique tropism enabling infection of mature T-cells, a process that critically depends on the interaction between viral glycoprotein gp350 and the cellular receptor CD21 [160]. Following infection, EBV-transformed T or NK-cells undergo proliferation supported by viral oncoproteins, most notably LMP1, which functions as a constitutive mimic of CD40. Through this mechanism, LMP1 persistently activates multiple signaling cascades, including the AKT, MAPK, JNK, STAT, and NF-κB pathways, thereby enhancing cell-cycle progression, inhibiting apoptosis, and modulating immune responses [161].
These EBV-infected cellular clusters also exhibit elevated expression of immune checkpoint molecules, including PD-L1 and CD86, which mediate profound immunosuppressive interactions with T cells via PD-L1/PD-1 and CD86/CTLA4 signaling axes. This observation suggests that LMP1 may represent a central driver of oncogenic transformation and tumor maintenance within EBV-associated T/NK-cell neoplasms. Furthermore, genomic instability induced by EBV infection contributes to the accumulation of somatic mutations in oncogenes and tumor suppressor genes, thereby promoting the emergence and evolution of EBV-driven T/NK-cell lymphomas [162].
Single-cell transcriptomic analyses have recently delineated at least three major LME phenotypic clusters with distinct immune compositions [163]. The LME1 cluster exhibits an immune-desert phenotype characterized by the absence of T and myeloid dendritic cells (MDCs). The LME2 cluster corresponds to an immune-deficient phenotype, displaying the presence of T and stromal cells but lacking MDCs, indicative of impaired innate immunity. In contrast, the LME3 cluster represents an immune-inflamed phenotype, distinguished by increased infiltration of both T cells and MDCs and associated with signatures of immune activation and exhaustion [163].
Across all three phenotypic clusters, dysregulation of G protein–coupled receptor (GPCR) signaling pathways has been observed, a process modulated by EBV that contributes to the remodeling of cancer immunity and promotes lymphoma progression.
Notably, overexpression of chemokine receptor 1 (CCR1) has been identified in LME1 and LME3, where it contributes to the modulation of immunosuppressive cell populations within the virus–cancer interface of the LME. These findings highlight CCR1 and related pathways as potential targets for therapeutic intervention.
EBV-infected lymphoma cells, together with surrounding stromal components, cooperatively remodel the ECM. This reorganization transforms the ECM into a permissive scaffold that fosters lymphoma cell survival, proliferation, and progression, thereby reinforcing the complex interplay between viral oncogenesis and the tumor microenvironment.

5.2. HTLV-1 as the T/NK-Cell Lymphoma Promoting Agent

In contrast to EBV, HTLV-1 is less ubiquitous and exhibits a geographically restricted endemic distribution, with high-prevalence clusters (>5% of tested individuals) in southwestern Japan, West Africa, Central and South America (notably Brazil), and the Caribbean [164]. Surrounding these clusters are intermediate (<5%) and low (~1%) prevalence regions, including the USA, Canada, Australia, Chile, Argentina, India, Iran, and several European countries [165]. These high-prevalence regions demonstrate unusually elevated incidence of ATLL across all four disease subtypes, reflecting a strong causal relationship between HTLV-1 infection and oncogenesis.
HTLV-1 encodes the viral transcriptional transactivator Tax in the pX region of its genome, which plays a central role in malignant transformation. Tax interacts with host cell proteins, modulates intracellular signaling pathways, regulates gene transcription, and drives proliferation of HTLV-1-infected T-cells [166,167]. In asymptomatic carriers, a balance exists between proliferation of infected T-cells and immune clearance by cytotoxic CD8+ T-cells. Expression of viral proteins renders HTLV-1-infected cells antigenic, provoking host immunity and necessitating multiple immune escape mechanisms during ATLL development [168,169]. Tax contributes to this immune evasion by modulating immune-related pathways that enhance survival.
Genetic alterations affecting the MHC class I complex (HLA-A, HLA-B, and β2-microglobulin) have been reported in 54% of ATLL cases, indicating that loss of MHC class I–mediated immune recognition is a critical step in pathogenesis [170]. ATLL cells retaining both MHC class I and β2-microglobulin exhibit better clinical outcomes compared to cases lacking these molecules [171]. MHC class II expression, regulated by the class II transactivator, is higher in indolent ATLL than in aggressive subtypes, suggesting a role in disease progression and serving as an independent favorable prognostic marker [172,173,174]. Interaction between MHC class II on tumor cells and CD4+ tumor-infiltrating lymphocytes (TILs) may further contribute to immune evasion [168].
Profound immunodeficiency is characteristic of ATLL, facilitating the accumulation of genetic abnormalities in immune-related genes and selection of clones capable of escaping host immunity. The ATLL LME demonstrates reduced cytotoxic CD8+ T cells and B cells, impaired NK-cell function, and expansion of myeloid populations [169]. Infiltration by lymphoma-associated macrophages (LAMs) supports malignant cell proliferation, invasion, angiogenesis, and immunosuppression, particularly in acute and lymphoma-type ATLL, correlating with poor prognosis [175]. CD47 expression on ATLL cells inhibits LAM phagocytosis via SIRPα signaling (“don’t eat me” signal), though its prognostic significance remains unclear; paradoxically, SIRPα expression on stromal cells is associated with favorable outcomes [176,177].
PD-L1 expression exhibits compartment-specific effects: PD-L1 on ATLL cells, particularly in nodal lesions, is linked to poor prognosis, whereas PD-L1 on stromal macrophages and dendritic cells correlates with improved outcomes, although its precise role in the LME remains undefined [178]. Peripheral blood analyses reveal decreased invariant NK-T, NK, and dendritic cell populations in ATLL patients [179], while single-cell studies show reduced B cells, increased myeloid cells, dendritic cells, and atypical monocytes with upregulated activation markers (CD64) and immune checkpoint molecules (PD-1) [180]. Despite B-cell reduction, interferon signaling is enhanced in myeloid cells, and cytotoxic CD8+ T-cell decline is associated with PD-L1 genetic alterations, which further modulate immune microenvironment composition [180]. Functional NK-cell defects are observed in both HTLV-1 carriers and ATLL patients, underscoring the critical role of immune microenvironment remodeling in HTLV-1–driven carcinogenesis [169,180].

6. Inflammation as a Significant Factor in T/NK-Cell Neoplasms

Inflammation in mature T/NK-cell neoplasms is not a secondary consequence of malignant transformation but a fundamental driver of disease pathogenesis. The WHO-HAEM5 and ICC 2022 classifications highlight the biological distinctiveness of EBV+ NK/T-cell lymphomas and HTLV-1–associated ATLL, both shaped by chronic antigenic stimulation [4,5]. Malignant cells exploit the inflammatory cytokine milieu—particularly IL-15, IL-6, and IL-21—to sustain proliferation and evade apoptosis within a deregulated microenvironment [181,182].
Key inflammatory pathways, including JAK/STAT and NF-κB, are activated either by somatic mutations (JAK3, STAT3, STAT5B) or by viral proteins. LMP1, encoded by EBV, induces PD-L1 expression through both JAK/STAT and NF-κB signaling, whereas the HTLV-1 Tax protein serves as a potent NF-κB activator in ATLL [8,9,183]. The immune microenvironment, actively remodeled by these interactions, fosters tumor progression via immune checkpoint upregulation and inflammatory cell recruitment [182].
Clinically, this inflammatory phenotype often manifests as hemophagocytic lymphohistiocytosis–like episodes, hyperferritinemia, and elevated soluble IL-2 receptor levels, particularly in EBV-driven diseases [184,185]. Collectively, the convergence of inflammatory mediators, viral oncogenic factors, and microenvironmental reprogramming defines a recurrent pathogenic theme in T/NK-cell malignancies, positioning the JAK/STAT and PD-L1 pathways as promising therapeutic targets [4,5,7,56,83,84,85,181,182,183,184,185].

6.1. Leukemic Entities

In NK-LGL, the bone marrow microenvironment exhibits a highly inflamed phenotype characterized by close interactions between DCs and NK-cells, which underpin persistent antigen presentation [186,187]. Cytokines play a dual role in this setting—not only sustaining inflammation but also supporting leukemic cell survival. For instance, IL-15, secreted by stromal and DCs, promotes NK-cell persistence, while IL-6 and TNF-α produced by leukemic cells reinforce JAK/STAT and NF-κB signaling [188,189]. Moreover, IFN-γ and TNF-α can induce apoptosis of hematopoietic progenitors, contributing to cytopenias such as neutropenia, further exacerbated by IL-8 and IL-10 [13,14,15]. The hyperactive immune milieu frequently manifests with autoimmune phenomena, including rheumatoid arthritis and pure red cell aplasia, strengthening the link between chronic inflammation and leukemogenesis [187,188,189].
T-LGL similarly arises in a state of sustained inflammation, wherein immune cells secrete IL-15, IL-2, and IL-6, perpetuating malignant T-LGL survival through continuous STAT3/5 and NF-κB activation [190,191]. IL-15 and its receptor complex are markedly upregulated, while JAK/STAT signaling is amplified via overexpression of IL-2R [190]. Concurrently, the PI3K/Akt/MAPK cascade is activated through autocrine IL-6/gp130 and PDGF signaling loops, and anti-apoptotic mediators such as c-FLIP inhibit Fas-induced cell death [191]. This cytokine-driven inflammatory network underlies the anemia, neutropenia, and autoimmune manifestations characteristic of T-LGL, reinforcing the notion that chronic inflammation sustains leukemic persistence [187,192].
A unifying hallmark across mature T/NK-cell neoplasms is their capacity for self-sustaining proliferation coupled with immune evasion, both orchestrated through inflammatory mechanisms. In T-PLL, dysregulation of the IL2RG–JAK1/3–STAT5B axis results in constitutive STAT activation, generating a permissive environment for clonal expansion and survival within an immunologically imbalanced milieu [193,194].
In ANKL, a prototypical EBV-associated malignancy, patients frequently develop hemophagocytic lymphohistiocytosis (HLH) with profound macrophage activation, hyperferritinemia, and consumptive coagulopathy. This cytokine storm not only causes tissue injury but also supports the proliferation of leukemic NK-cells [121,194,195]. Immune escape in ANKL is further promoted by PD-L1 upregulation mediated through NF-κB and STAT3 activation [194,196,197].
Finally, in ATLL viral oncoproteins Tax and HBZ activate the NF-κB and AP-1 pathways, profoundly altering host immune regulation. Elevated IL-2 and IL-15 levels foster a pro-inflammatory microenvironment, whereas increased IL-10 drives a STAT3/IRF4-dependent positive feedback loop in leukemic T-cells, enhancing proliferation and immune evasion [198,199].

6.2. Nodal Lymphomas

Nodal TFH-cell lymphomas share a characteristic inflammatory microenvironment, where immune dysregulation drives both local and systemic inflammatory symptoms [200,201]. Affected lymph nodes display dense infiltrates of T cells, plasma cells, dendritic cells (DCs), and macrophages, supported by extensive follicular DC and endothelial venule networks [200]. Neoplastic TFH cells secrete IL-21 and CXCL13, stimulating germinal-center B-cell and follicular DC expansion, leading to polyclonal plasmacytosis, hypergammaglobulinemia, and Treg depletion [200,201]. IL-6 provides additional pro-survival signaling, while the accompanying cytokine storm manifests clinically with fever, rash, and weight loss [202].
PTCL-NOS and ALK+/ALK− ALCL exhibit highly reactive microenvironments dominated by LAMs, which support tumor growth and suppress cytotoxic responses [203,204]. IL-10 activates STAT3 and inhibits DC maturation, while TGF-β reinforces immunosuppression [203,205]. In ALK+ ALCL, the nucleophosmin (NPM)-ALK fusion constitutively activates STAT3, inducing IL-6, IL-10, and TGF-β secretion and promoting PD-L1 expression [32,33,34,206,207,208]. In ALK− ALCL, JAK1/STAT3 mutations drive similar effects, with PD-L1 expression also present on LAMs [34]. CD30-TRAF-NF-κB signaling and IRF4 cooperatively sustain cytokine production and tumor persistence [209].
PTCL-NOS comprises distinct molecular subgroups: GATA3-driven cases produce IL-4, IL-5, IL-13, and IL-10, with eosinophil/macrophage-rich infiltrates and poorer outcomes, whereas TBX21-high cases, marked by abundant IFN-γ, are associated with a more favorable prognosis [30,36,202,204].

6.3. Extranodal Lymphomas

Primary cutaneous acral CD8+ lymphoproliferative disorder is an indolent condition characterized by a localized proliferation of CD8+ T cells, typically affecting acral skin sites [210]. Histology reveals dense dermal infiltrates enriched in dendritic cells (DCs), macrophages, plasma cells, and eosinophils [38]. CD8+ T cells secrete IFN-γ and TNF-α, activating macrophages, while IL-2 supports local proliferation [211]. Macrophage-derived IL-10 suppresses DC activity, fostering immune tolerance and explaining the disease’s indolent, skin-limited course and lack of EBV association [210,211,212,213].
Intestinal T- and NK-cell lymphoid proliferations and lymphomas encompass entities driven by inflammatory mechanisms and mucosal immune activation [214]. EATL is closely linked to celiac disease, where gluten-induced IL-15 elevation, Treg suppression, and IFN-γ–mediated mucosal injury drive JAK/STAT activation [214,215]. MEITL, in contrast, arises de novo, features monomorphic epitheliotropism with minimal inflammation, and may exhibit necrosis [216]. Indolent intestinal T-cell proliferations occur in the context of IBD or immunosuppression, while their NK counterpart, indolent NK-cell enteropathy, remains EBV-negative, non-destructive, and mucosa-confined [10,217]. Shared mechanisms—IL-2, IL-15, TNF, and IFN-γ signaling—promote immune dysregulation and clonal persistence [10,214,215].
Indolent T-cell lymphoma of the gastrointestinal tract similarly shows a slow course with prominent mucosal inflammation. IBD and immunosuppression sustain small CD4+/CD8+ T-cell expansion via IL-15 and IFN-γ signaling, supporting chronic proliferation without systemic spread [218].
ENKTCL, by contrast, is an aggressive EBV-driven neoplasm marked by a cytokine-rich microenvironment and chronic inflammation [141]. Elevated serum IL-6, IL-10, survivin, and VEGF correlate with poor prognosis [219,220,221]. EBV induces a cytokine storm dominated by IFN-γ, IL-6, and IL-10, fostering systemic inflammation and PD-L1 expression that enhances immune evasion. A pathogenic feedback loop between viral activity and inflammatory mediators underlies ENKTCL progression [85,222].

6.4. Provisional/Childhood EBV-Driven Entities

Among EBV-driven malignancies, hydroa vacciniforme–like lymphoproliferative disorder (HV-LPD) represents a prototypical example [4,5]. Lesions contain EBV-infected CD8+ T and NK-cells, as well as type I and γδ T-cells [223]. The microenvironment is highly inflamed, with elevated IFN-γ and TNF-α driving keratinocyte apoptosis and recruitment of lymphocytes via chemokines CXCL9 and CXCL10 [223]. High IL-10 levels, secreted by macrophages and infected cells, confer local immunosuppression that counterbalances cytotoxic activity. Activation of the JAK/STAT and NF-κB pathways within this pro- and anti-inflammatory equilibrium underlies the chronic course of HV-LPD and the long-term survival of EBV-infected cells.
Systemic chronic active EBV disease (CAEBV) is another EBV-driven T/NK-cell disorder classified under EBV+ T/NK-cell lymphoid proliferations in WHO-HAEM5 [4]. It primarily involves the liver and lymph nodes, where EBV-infected cells form granulomas and portal infiltrates, resulting in chronic immune activation [224]. Elevated IL-6, TNF-α, and IFN-γ drive systemic inflammation and hemophagocytic episodes, while IL-10 promotes immune evasion and EBV persistence [225,226]. Upregulation of PD-1 and PD-L1 further contributes to immune escape [224]. Clinically, cytokine storm–mediated manifestations include cytopenia, hepatosplenomegaly, hyperferritinemia, and increased soluble IL-2 receptor levels [226,227].

7. Conclusions

Based on this comprehensive overview, a substantial paradigm shift is emerging in our understanding of neoplastic tissue homeostasis, particularly within the context of T/NK-cell neoplasms. The accumulating evidence indicates that these malignancies should no longer be regarded merely as aggregates of neoplastic lymphoid cells, but rather as complex, multicellular ecosystems composed of a heterogeneous admixture of stromal and immune elements intimately interwoven with lymphoma cells and the extracellular matrix. Accordingly, T/NK-cell neoplasms ought to be conceptualized as dynamic, interactive, and adaptable biological systems, responsive to a spectrum of endogenous and exogenous cues that collectively shape their behavior and evolution.
This reconceptualization provides critical insight into the pronounced clinical heterogeneity observed among T/NK-cell lymphomas, underscoring the pivotal role of LME composition in determining disease course and therapeutic response. Current data suggest that lymphomas characterized by an immune-rich stroma and elevated PD-L1/PD-1 expression are more likely to benefit from immune checkpoint inhibition (ICI), whereas those exhibiting an immune-desert phenotype may instead require therapeutic strategies directed against specific oncogenic drivers.
Advances in matrix biology are expected to catalyze the development of an expanding repertoire of targeted anti-lymphoma therapies. Beyond conventional cytotoxic regimens, the emerging vision encompasses the selective modulation of multiple molecular and cellular pathways, representing a transformative step toward personalized treatment paradigms in T/NK-cell lymphomas. While considerable progress has been made in elucidating the molecular biology of these tumors, the field remains unbalanced, and additional time and research are needed for full clinical applicability. Ultimately, the integration of high-quality, evidence-based molecular and microenvironmental markers into standard prognostic models and therapeutic algorithms promises to establish them as robust and clinically actionable tools in routine practice [228].

Author Contributions

Conceptualization, I.P.; writing—original draft preparation, I.P., M.R. (Michele Ritucci), A.S., S.S. and A.P.; writing—review and editing, I.P. and S.S.; visualization, I.C. and M.R. (Michele Ritucci); supervision, I.P., I.C., M.R. (Milica Radić), M.D. and M.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

During the preparation of this manuscript/study, the author(s) used ChatGPT version 4 for the purposes of improving English language (Editing). The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Petković, I.; Popović, A.; Džunić, M.; Pejčić, I. Nodal and extranodal peripheral T/NK-cell neoplasms: Current aspects. Acta Fac. Med. Naissensis 2020, 37, 99–120. [Google Scholar] [CrossRef]
  2. Montes-Mojarro, I.A.; Fend, F.; Quintanilla-Martinez, L. EBV and the Pathogenesis of NK/T Cell Lymphoma. Cancers 2021, 13, 1414. [Google Scholar] [CrossRef]
  3. Lin, G.W.; Xu, C.; Chen, K.; Huang, H.Q.; Chen, J.; Song, B.; Chan, J.K.C.; Li, W.; Liu, W.; Shih, L.Y.; et al. Genetic risk of extranodal natural killer T-cell lymphoma: A genome-wide association study in multiple populations. Lancet Oncol. 2020, 21, 306–316. [Google Scholar] [CrossRef]
  4. Alaggio, R.; Amador, C.; Anagnostopoulos, I.; Attygalle, A.D.; Araujo, I.B.O.; Berti, E.; Bhagat, G.; Borges, A.M.; Boyer, D.; Calaminici, M.; et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022, 36, 1720–1748, Erratum in Leukemia 2023, 37, 1944–1951. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  5. Campo, E.; Jaffe, E.S.; Cook, J.R.; Quintanilla-Martinez, L.; Swerdlow, S.H.; Anderson, K.C.; Brousset, P.; Cerroni, L.; de Leval, L.; Dirnhofer, S.; et al. The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee. Blood 2022, 140, 1229–1253, Erratum in Blood 2023, 141, 437. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  6. Attygalle, A.D.; Karube, K.; Jeon, Y.K.; Cheuk, W.; Bhagat, G.; Chan, J.K.C.; Naresh, K.N. The fifth edition of the WHO classification of mature T cell, NK cell and stroma-derived neoplasms. J. Clin. Pathol. 2025, 78, 217–232. [Google Scholar] [CrossRef] [PubMed]
  7. Oishi, N.; Ahmed, R.; Feldman, A.L. Updates in the Classification of T-cell Lymphomas and Lymphoproliferative Disorders. Curr. Hematol. Malig. Rep. 2023, 18, 252–263. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  8. Asano, N.; Suzuki, R.; Kagami, Y.; Ishida, F.; Kitamura, K.; Fukutani, H.; Morishima, Y.; Takeuchi, K.; Nakamura, S. Clinicopathologic and prognostic significance of cytotoxic molecule expression in nodal peripheral T-cell lymphoma, unspecified. Am. J. Surg. Pathol. 2005, 29, 1284–1293. [Google Scholar] [CrossRef]
  9. Swerdlow, S.H.; Jaffe, E.S.; Brousset, P.; Chan, J.K.; de Leval, L.; Gaulard, P. International Lymphoma Study Group. Cytotoxic T-cell and NK-cell lymphomas: Current questions and controversies. Am. J. Surg. Pathol. 2014, 38, e60–e71. [Google Scholar] [CrossRef] [PubMed]
  10. Perry, A.M.; Warnke, R.A.; Hu, Q.; Gaulard, P.; Copie-Bergman, C.; Alkan, S.; Wang, H.-Y.; Cheng, J.X.; Bacon, C.M.; Delabie, J.; et al. Indolent T-cell lymphoproliferative disease of the gastrointestinal tract. Blood 2013, 122, 3599–3606. [Google Scholar] [CrossRef] [PubMed]
  11. Petrella, T.; Maubec, E.; Cornillet-Lefebvre, P.; Willemze, R.; Pluot, M.; Durlach, A. Indolent CD8-positive lymphoid proliferation of the ear: A distinct primary cutaneous T-cell lymphoma. Am. J. Surg. Pathol. 2007, 31, 1887–1892. [Google Scholar] [CrossRef]
  12. Sun, J.C.; Lanier, L.L. NK cell development, homeostasis and function: Parallels with CD8 T cells. Nat. Rev. Immunol. 2011, 11, 645–657. [Google Scholar] [CrossRef]
  13. Lanier, L.L.; Testi, R.; Bindl, J.; Phillips, J.H. Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. J. Exp. Med. 1989, 169, 2233–2238. [Google Scholar] [CrossRef]
  14. Chan, J.K.; Tsang, W.Y.; Ng, C.S. Clarification of CD3 immunoreactivity in nasal T/natural killer cell lymphomas: The neoplastic cells are often CD3 epsilon+. Blood 1996, 87, 839–841. [Google Scholar] [CrossRef]
  15. de Leval, L.; Rickman, D.S.; Thielen, C.; de Reynies, A.; Huang, Y.-L.; Delsol, G.; Lamant, L.; Leroy, K.; Brière, J.; Molina, T.; et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 2007, 109, 4952–4963. [Google Scholar] [CrossRef] [PubMed]
  16. Iqbal, J.; Weisenburger, D.D.; Greiner, T.C.; Vose, J.M.; McKeithan, T.; Kucuk, C.; Geng, H.; Deffenbacher, K.; Smith, L.; Dybkaer, K.; et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 2010, 115, 1026–1036. [Google Scholar] [CrossRef]
  17. Zhang, M.; Zhang, B. Extracellular matrix stiffness: Mechanisms in tumor progression and therapeutic potential in cancer. Exp. Hematol. Oncol. 2025, 14, 54. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  18. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed]
  19. Hong, J.; Jin, H.J.; Choi, M.R.; Lim, D.W.; Park, J.E.; Kim, Y.S.; Lim, S.B. Matrisomics: Beyond the extracellular matrix for unveiling tumor microenvironment. Biochim. Biophys. Acta Rev. Cancer 2024, 1879, 189178. [Google Scholar] [CrossRef]
  20. Bangham, C.R.M. HTLV-1 persistence and the oncogenesis of adult T-cell leukemia/lymphoma. Blood 2023, 141, 2299–2306. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  21. Ribatti, D.; Tamma, R.; Annese, T.; Ingravallo, G.; Specchia, G. Macrophages and angiogenesis in human lymphomas. Clin. Exp. Med. 2024, 24, 26. [Google Scholar] [CrossRef]
  22. Wang, T.; Feldman, A.L.; Wada, D.A.; Lu, Y.; Polk, A.; Briski, R.; Ristow, K.; Habermann, T.M.; Thomas, D.; Ziesmer, S.C.; et al. GATA-3 expression identifies a high-risk subset of PTCL-NOS with distinct molecular and clinical features. Blood 2014, 123, 3007–3015. [Google Scholar] [CrossRef] [PubMed]
  23. Chanmee, T.; Ontong, P.; Konno, K.; Itano, N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 2014, 6, 1670–1690. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  24. Tse, E.; Kwong, Y.L. T-cell lymphoma: Microenvironment-related biomarkers. Semin. Cancer Biol. 2015, 34, 46–51. [Google Scholar] [CrossRef] [PubMed]
  25. Xie, Y.; Jaffe, E.S. How I Diagnose Angioimmunoblastic T-Cell Lymphoma. Am. J. Clin. Pathol 2021, 156, 1–14. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  26. Pasca, S.; Jurj, A.; Matei, D. Angioimmunoblastic T-cell Lymphoma Microenvironment. Arch. Cancer Biol. Ther. 2020, 1, 11–13. [Google Scholar]
  27. Zhao, W.L.; Mourah, S.; Mounier, N.; Leboeuf, C.; Daneshpouy, M.E.; Legrès, L.; Meignin, V.; Oksenhendler, E.; Maignin, C.L.; Calvo, F.; et al. Vascular endothelial growth factor-A is expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression. Lab. Investig. 2004, 84, 1512–1519. [Google Scholar] [CrossRef] [PubMed]
  28. Jørgensen, J.M.; Sørensen, F.B.; Bendix, K.; Nielsen, J.L.; Funder, A.; Karkkainen, M.J.; Tainola, T.; Sørensen, A.B.; Pedersen, F.S.; D’Amore, F. Expression level, tissue distribution pattern, and prognostic impact of vascular endothelial growth factors VEGF and VEGF-C and their receptors Flt-1, KDR, and Flt-4 in different subtypes of non-Hodgkin lymphomas. Leuk. Lymphoma 2009, 50, 1647–1660. [Google Scholar] [CrossRef]
  29. Huang, W.; Cao, Z.; Zeng, L.; Guo, L.; Liu, X.; Lv, N.; Feng, X. nm23, TOP2A and VEGF expression: Potential prognostic biologic factors in peripheral T-cell lymphoma, not otherwise specified. Oncol. Lett. 2019, 18, 3803–3810. [Google Scholar] [CrossRef]
  30. Huang, Y.; de Reyniès, A.; de Leval, L.; Ghazi, B.; Martin-Garcia, N.; Travert, M.; Bosq, J.; Brière, J.; Petit, B.; Thomas, E.; et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood 2010, 115, 1226–1237. [Google Scholar] [CrossRef]
  31. Ni, M.; Wang, Y.; Yang, J.; Ma, Q.; Pan, W.; Li, Y.; Xu, Q.; Lv, H.; Wang, Y. IL-33 aggravates extranodal NK/T cell lymphoma aggressiveness and angiogenesis by activating the Wnt/β-catenin signaling pathway. Mol. Cell Biochem. 2025, 480, 265–278. [Google Scholar] [CrossRef]
  32. Tamma, R.; Ingravallo, G.; Annese, T.; Gaudio, F.; Perrone, T.; Musto, P.; Specchia, G.; Ribatti, D. Tumor microenvironment and microvascular density in follicular lymphoma. J. Clin. Med. 2022, 11, 1257. [Google Scholar] [CrossRef]
  33. Mazur, G.; Woźniak, Z.; Wróbel, T.; Maj, J.; Kuliczkowski, K. Increased angiogenesis in cutaneous T-cell lymphomas. Pathol. Oncol. Res. 2004, 10, 34–36. [Google Scholar] [CrossRef]
  34. Ganjoo, K.; Hong, F.; Horning, S.J.; Gascoyne, R.D.; Natkunam, Y.; Swinnen, L.J.; Habermann, T.M.; Kahl, B.S.; Advani, R.H. Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: An Eastern Cooperative Oncology Group study (E2404). Leuk. Lymphoma 2014, 55, 768–772. [Google Scholar] [CrossRef]
  35. Ribatti, D.; Tamma, R.; Annese, T.; d’Amati, A.; Ingravallo, G.; Specchia, G. Vascular growth in lymphomas: Angiogenesis and alternative ways. Cancers 2023, 15, 3262. [Google Scholar] [CrossRef] [PubMed]
  36. Gloger, M.; Menzel, L.; Grau, M.; Vion, A.C.; Anagnostopoulos, I.; Zapukhlyak, M.; Gerlach, K.; Kammertöns, T.; Hehlgans, T.; Zschummel, M.; et al. Lymphoma Angiogenesis Is Orchestrated by Noncanonical Signaling Pathways. Cancer Res. 2020, 80, 1316–1329. [Google Scholar] [CrossRef] [PubMed]
  37. Strioga, M.; Schijns, V.; Powell, D.J., Jr.; Pasukoniene, V.; Dobrovolskiene, N.; Michalek, J. Dendritic cells and their role in tumor immunosurveillance. Innate Immun. 2013, 19, 98–111. [Google Scholar] [CrossRef]
  38. Li, Y.Q.; Luo, C.L.; Jiang, J.X.; He, S.; Liu, Y.; Yan, W.X.; Xia, Y.; Cui, Q.; Huang, Y.; Lim, J.Q.; et al. Single-Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T-Cell Lymphoma. Adv. Sci. 2023, 10, e2303913. [Google Scholar] [CrossRef]
  39. Wallet, M.A.; Sen, P.; Tisch, R. Immunoregulation of dendritic cells. Clin. Med. Res. 2005, 3, 166–175. [Google Scholar] [CrossRef]
  40. Raaijmakers, T.K.; Ansems, M. Microenvironmental derived factors modulating dendritic cell function and vaccine efficacy: The effect of prostanoid receptor and nuclear receptor ligands. Cancer Immunol. Immunother. 2018, 67, 1789–1796. [Google Scholar] [CrossRef]
  41. Tan, J.K.; O’Neill, H.C. Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity. J. Leukoc. Biol. 2005, 78, 319–324. [Google Scholar] [CrossRef]
  42. Svajger, U.; Rozman, P. Tolerogenic dendritic cells: Molecular and cellular mechanisms in transplantation. J. Leukoc. Biol. 2014, 95, 53–69. [Google Scholar] [CrossRef] [PubMed]
  43. Kushwah, R.; Hu, J. Role of dendritic cells in the induction of regulatory T cells. Cell Biosci. 2011, 1, 20. [Google Scholar] [CrossRef] [PubMed]
  44. Curti, A.; Trabanelli, S.; Salvestrini, V.; Baccarani, M.; Lemoli, R.M. The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: Focus on hematology. Blood 2009, 113, 2394–2401. [Google Scholar] [CrossRef]
  45. Idoyaga, J.; Moreno, J.; Bonifaz, L. Tumor cells prevent mouse dendritic cell maturation induced by TLR ligands. Cancer Immunol. Immunother. 2007, 56, 1237–1250. [Google Scholar] [CrossRef]
  46. Scheuerpflug, A.; Ahmetlić, F.; Bauer, V.; Riedel, T.; Röcken, M.; Mocikat, R. The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors. Cancer Immunol. Immunother. 2021, 70, 1343–1350. [Google Scholar] [CrossRef] [PubMed]
  47. Moon, C.Y.; Belabed, M.; Park, M.D.; Mattiuz, R.; Puleston, D.; Merad, M. Dendritic cell maturation in cancer. Nat. Rev. Cancer 2025, 25, 225–248. [Google Scholar] [CrossRef]
  48. Marciscano, A.E.; Anandasabapathy, N. The role of dendritic cells in cancer and anti-tumor immunity. Semin. Immunol. 2021, 52, 101481. [Google Scholar] [CrossRef]
  49. Kumar, D.; Xu, M.L. Microenvironment Cell Contribution to Lymphoma Immunity. Front. Oncol. 2018, 8, 288, Erratum in Front. Oncol. 2018, 8, 522. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  50. Park, J.E.; Dutta, B.; Tse, S.W.; Gupta, N.; Tan, C.F.; Low, J.K.; Yeoh, K.W.; Kon, O.L.; Tam, J.P.; Sze, S.K. Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift. Oncogene 2019, 38, 5158–5173. [Google Scholar] [CrossRef]
  51. Mantovani, A.; Sica, A.; Sozzani, S.; Allavena, P.; Vecchi, A.; Locati, M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004, 25, 677–686. [Google Scholar] [CrossRef] [PubMed]
  52. Xiong, X.; Xie, X.; Wang, Z.; Zhang, Y.; Wang, L. Tumor-associated macrophages in lymphoma: From mechanisms to therapy. Int. Immunopharmacol. 2022, 112, 109235. [Google Scholar] [CrossRef] [PubMed]
  53. Barbera-Guillem, E.; Nyhus, J.K.; Wolford, C.C.; Friece, C.R.; Sampsel, J.W. Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res. 2002, 62, 7042–7049. [Google Scholar]
  54. Mishra, A.K.; Banday, S.; Bharadwaj, R.; Ali, A.; Rashid, R.; Kulshreshtha, A.; Malonia, S.K. Macrophages as a Potential Immunotherapeutic Target in Solid Cancers. Vaccines 2022, 11, 55. [Google Scholar] [CrossRef]
  55. Wang, L.; Zheng, G. Macrophages in leukemia microenvironment. Blood Sci. 2019, 1, 29–33. [Google Scholar] [CrossRef]
  56. Bi, X.W.; Wang, H.; Zhang, W.W.; Wang, J.H.; Liu, W.J.; Xia, Z.J.; Huang, H.Q.; Jiang, W.Q.; Zhang, Y.J.; Wang, L. PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma. J. Hematol. Oncol. 2016, 9, 109. [Google Scholar] [CrossRef] [PubMed]
  57. Moyano, A.; Ferressini, N.; De Matteo, E.; Preciado, M.V.; Chabay, P. PD-L1 is upregulated in CD163+ tonsillar macrophages from children undergoing EBV primary infection. Front. Immunol. 2022, 13, 940910. [Google Scholar] [CrossRef]
  58. Xu, X.; Li, Z.; Liu, J.; Zhu, F.; Wang, Z.; Wang, J. The prognostic value of tumour-associated macrophages in Non-Hodgkin’s lymphoma: A systematic review and meta-analysis. Scand. J. Immunol. 2020, 91, e12814. [Google Scholar] [CrossRef]
  59. Lin, Z.X.; Bai, B.; Cai, Q.C.; Cai, Q.Q.; Wang, X.X.; Wu, X.Y.; Huang, H.Q. High numbers of tumor-associated macrophages correlate with poor prognosis in patients with mature T- and natural killer cell lymphomas. Med. Oncol. 2012, 29, 3522–3528. [Google Scholar] [CrossRef]
  60. Bai, B.; Huang, H.Q.; Cai, Q.C.; Wang, X.X.; Cai, Q.; Gao, Y.; Zhao, W. The Activation Of M2 Polarized Tumor-Associated Macrophages in the Microenvironment of NK/T-Cell Lymphoma and the Characteristics of Cytokine Spectrum. Blood 2013, 122, 4274. [Google Scholar] [CrossRef]
  61. Gao, X.; Kady, N.; Wang, C.; Abdelrahman, S.; Gann, P.; Sverdlov, M.; Wolfe, A.; Brown, N.; Reneau, J.; Robida, A.M.; et al. Targeting Lymphoma-associated Macrophage Expansion via CSF1R/JAK Inhibition is a Therapeutic Vulnerability in Peripheral T-cell Lymphomas. Cancer Res. Commun. 2022, 2, 1727–1737. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  62. Pittenger, M.F.; Discher, D.E.; Péault, B.M.; Phinney, D.G.; Hare, J.M.; Caplan, A.I. Mesenchymal stem cell perspective: Cell biology to clinical progress. npj Regen. Med. 2019, 4, 22. [Google Scholar] [CrossRef]
  63. Hazrati, A.; Malekpour, K.; Khorramdelazad, H.; Rajaei, S.; Hashemi, S.M. Therapeutic and immunomodulatory potentials of mesenchymal stromal/stem cells and immune checkpoints related molecules. Biomark. Res. 2024, 12, 35. [Google Scholar] [CrossRef]
  64. Hazrati, A.; Soudi, S.; Malekpour, K.; Mahmoudi, M.; Rahimi, A.; Hashemi, S.M.; Varma, R.S. Immune cells-derived exosomes function as a double-edged sword: Role in disease progression and their therapeutic applications. Biomark. Res. 2022, 10, 30. [Google Scholar] [CrossRef]
  65. Peled, A.; Klein, S.; Beider, K.; Burger, J.A.; Abraham, M. Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine 2018, 109, 11–16. [Google Scholar] [CrossRef]
  66. Ramuta, T.Z.; Kreft, M.E. Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells. Cancers 2022, 14, 3761. [Google Scholar] [CrossRef] [PubMed]
  67. Liu, P.; Sun, Z. Chemokines and their receptors in the esophageal carcinoma tumor microenvironment: Key factors for metastasis and progression. Front. Oncol. 2025, 15, 1523751. [Google Scholar] [CrossRef]
  68. Shangguan, L.; Li, X.; Wang, Z.; Luo, Z. Transforming growth factor-β1 induces bone marrow-derived mesenchymal stem cells to differentiate into cancer-associated fibroblasts. Zhonghua Zhong Liu Za Zhi 2015, 37, 804–809. [Google Scholar]
  69. Ahn, S.Y. The Role of MSCs in the Tumor Microenvironment and Tumor Progression. Anticancer. Res. 2020, 40, 3039–3047. [Google Scholar] [CrossRef]
  70. Monu, N.R.; Frey, A.B. Myeloid-derived suppressor cells and anti-tumor T cells: A complex relationship. Immunol. Investig. 2012, 41, 595–613. [Google Scholar] [CrossRef] [PubMed]
  71. Zhang, H.; Li, Z.L.; Ye, S.B.; Ouyang, L.Y.; Chen, Y.S.; He, J.; Huang, H.Q.; Zeng, Y.X.; Zhang, X.S.; Li, J. Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: A novel prognostic indicator. Cancer Immunol. Immunother. 2015, 64, 1587–1599. [Google Scholar] [CrossRef]
  72. Papafragkos, I.; Markaki, E.; Kalpadakis, C.; Verginis, P. Decoding the Myeloid-Derived Suppressor Cells in Lymphoid Malignancies. J. Clin. Med. 2021, 10, 3462. [Google Scholar] [CrossRef] [PubMed]
  73. Whittingham, S.; Naselli, G.; Harrison, L.C.; Boyd, A.W.; Cebon, J.; Jack, I. Cytokine production in response to Epstein-Barr virus infection of peripheral blood mononuclear cells in vitro. Immunol. Cell Biol. 1993, 71 Pt 4, 259–264. [Google Scholar] [CrossRef]
  74. Rodríguez, P.C.; Ochoa, A.C. Arginine Regulation by Myeloid Derived Suppressor Cells and Tolerance in Cancer: Mechanisms and Therapeutic Perspectives. Immunol. Rev. 2008, 222, 180–191. [Google Scholar] [CrossRef] [PubMed]
  75. Rodriguez, P.C.; Zea, A.H.; Culotta, K.S.; Zabaleta, J.; Ochoa, J.B.; Ochoa, A.C. Regulation of T cell receptor CD3zeta chain expression by L-arginine. J. Biol. Chem. 2002, 277, 21123–21129. [Google Scholar] [CrossRef]
  76. Rodriguez, P.C.; Quiceno, D.G.; Ochoa, A.C. L-Arginine Availability Regulates T-Lymphocyte Cell-Cycle Progression. Blood 2007, 109, 1568–1573. [Google Scholar] [CrossRef] [PubMed]
  77. Mazzoni, A.; Bronte, V.; Visintin, A.; Spitzer, J.H.; Apolloni, E.; Serafini, P.; Zanovello, P.; Segal, D.M. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 2002, 168, 689–695. [Google Scholar] [CrossRef]
  78. Liu, M.; Wang, X.; Wang, L.; Ma, X.; Gong, Z.; Zhang, S.; Li, Y. Targeting the IDO1 Pathway in Cancer: From Bench to Bedside. J. Hematol. Oncol. 2018, 11, 100. [Google Scholar] [CrossRef]
  79. Corzo, C.A.; Cotter, M.J.; Cheng, P.; Cheng, F.; Kusmartsev, S.; Sotomayor, E.; Padhya, T.; McCaffrey, T.V.; McCaffrey, J.C.; Gabrilovich, D.I. Mechanism Regulating Reactive Oxygen Species in Tumor-Induced Myeloid-Derived Suppressor Cells. J. Immunol. 2009, 182, 5693–5701. [Google Scholar] [CrossRef]
  80. Huang, B.; Pan, P.Y.; Li, Q.; Sato, A.I.; Levy, D.E.; Bromberg, J.; Divino, C.M.; Chen, S.H. Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host. Cancer Res. 2006, 66, 1123–1131. [Google Scholar] [CrossRef]
  81. Cioccarelli, C.; Molon, B. MDSCs and T cells in solid tumors and non-Hodgkin lymphomas: An immunosuppressive speech. Clin. Exp. Immunol. 2022, 208, 147–157. [Google Scholar] [CrossRef]
  82. Mukherjee, P.; Ansell, S.M.; Mondello, P. Unravelling the role of cancer-associated fibroblasts in B cell lymphoma. Front. Immunol. 2024, 15, 1451791. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  83. Küçük, C.; Jiang, B.; Hu, X.; Zhang, W.; Chan, J.K.; Xiao, W.; Lack, N.; Alkan, C.; Williams, J.C.; Avery, K.N.; et al. Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nat. Commun. 2015, 6, 6025. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  84. Song, T.L.; Nairismägi, M.L.; Laurensia, Y.; Lim, J.Q.; Tan, J.; Li, Z.M.; Pang, W.L.; Kizhakeyil, A.; Wijaya, G.C.; Huang, D.C.; et al. Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood 2018, 132, 1146–1158. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  85. Jo, J.C.; Kim, M.; Choi, Y.; Kim, H.J.; Kim, J.E.; Chae, S.W.; Kim, H.; Cha, H.J. Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type. Ann. Hematol. 2017, 96, 25–31. [Google Scholar] [CrossRef] [PubMed]
  86. Komi, D.E.A.; Redegeld, F.A. Role of Mast Cells in Shaping the Tumor Microenvironment. Clin. Rev. Allergy Immunol. 2020, 58, 313–325. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  87. Cho, J.; Kim, S.J.; Park, W.Y.; Kim, J.; Woo, J.; Kim, G.; Yoon, S.E.; Ko, Y.H.; Kim, W.S. Immune subtyping of extranodal NK/T-cell lymphoma: A new biomarker and an immune shift during disease progression. Mod. Pathol. 2020, 33, 603–615. [Google Scholar] [CrossRef]
  88. Du, Y.; Cai, Y.; Lv, Y.; Zhang, L.; Yang, H.; Liu, Q.; Hong, M.; Teng, Y.; Tang, W.; Ma, R.; et al. Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma. Cancer Lett. 2022, 551, 215972. [Google Scholar] [CrossRef] [PubMed]
  89. Krejsgaard, T.; Lindahl, L.M.; Mongan, N.P.; Wasik, M.A.; Litvinov, I.V.; Iversen, L.; Langhoff, E.; Woetmann, A.; Odum, N. Malignant inflammation in cutaneous T-cell lymphoma-a hostile takeover. Semin. Immunopathol. 2017, 39, 269–282. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  90. Maharaj, K.; Uriepero, A.; Sahakian, E.; Pinilla-Ibarz, J. Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies. Front. Immunol. 2022, 13, 943354. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  91. Wang, J.; Ke, X.Y. The four types of Tregs in malignant lymphomas. J. Hematol. Oncol. 2011, 4, 50. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  92. Gaulard, P.; de Leval, L. Follicular helper T cells: Implications in neoplastic hematopathology. Semin. Diagn. Pathol. 2011, 28, 202–213. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  93. de Mel, S.; Li, J.B.; Abid, M.B.; Tang, T.P.L.; Tay, H.M.; Ting, W.C.; Poon, L.M.; Chung, T.H.; Mow, B.; Tso, A.; et al. The Utility of Flow Cytometry in Differentiating NK/T Cell Lymphoma from Indolent and Reactive NK Cell Proliferations. Cytom. Part B 2018, 94B, 159–168. [Google Scholar] [CrossRef]
  94. Lin, C.W.; Lee, W.H.; Chang, C.L.; Yang, J.Y.; Hsu, S.M. Restricted killer cell immunoglobulin-like receptor repertoire without T-cell receptor gamma rearrangement supports a true natural killer-cell lineage in a subset of sinonasal lymphomas. Am. J. Pathol. 2001, 159, 1671–1679. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  95. Scheffschick, A.; Nenonen, J.; Xiang, M.; Winther, A.H.; Ehrström, M.; Wahren-Herlenius, M.; Eidsmo, L.; Brauner, H. Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor. Front. Immunol. 2023, 14, 1168684. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  96. Barreira da Silva, R.; Laird, M.E.; Yatim, N.; Fiette, L.; Ingersoll, M.A.; Albert, M.L. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat. Immunol. 2015, 16, 850–858. [Google Scholar] [CrossRef] [PubMed]
  97. de Mel, S.; Hue, S.S.; Jeyasekharan, A.D.; Chng, W.J.; Ng, S.B. Molecular pathogenic pathways in extranodal NK/T cell lymphoma. J. Hematol. Oncol. 2019, 12, 33. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  98. Tse, E.; Zhao, W.L.; Xiong, J.; Kwong, Y.L. How we treat NK/T-cell lymphomas. J. Hematol. Oncol. 2022, 15, 74. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  99. Kwong, Y.L.; Chan, T.S.Y.; Tan, D.; Kim, S.J.; Poon, L.M.; Mow, B.; Khong, P.L.; Loong, F.; Au-Yeung, R.; Iqbal, J.; et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood 2017, 129, 2437–2442. [Google Scholar] [CrossRef]
  100. Li, X.; Cheng, Y.; Zhang, M.; Yan, J.; Li, L.; Fu, X.; Zhang, X.; Chang, Y.; Sun, Z.; Yu, H.; et al. Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J. Hematol. Oncol. 2018, 11, 15. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  101. Zhang, W.; Liu, M.; Li, W.; Song, Y. Immune cells in the B-cell lymphoma microenvironment: From basic research to clinical applications. Chin. Med. J. 2024, 137, 776–790. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  102. Tan, R.; Nie, M.; Long, W. The role of B cells in cancer development. Front. Oncol. 2022, 12, 958756. [Google Scholar] [CrossRef]
  103. Petković, I.; Stojnev, S.; Popović, A.; Krstić, M.; Pejčić, I. EBV Negative Angioimmunoblastic T-Cell Lymphoma with Sequential Development of Diffuse Large B-Cell Lymphoma in Course of Progression. Indian J. Hematol. Blood Transfus. 2021, 37, 694–696. [Google Scholar] [CrossRef] [PubMed]
  104. Kim, H.N.; Kim, D.S.; Jeon, M.J.; Yu, E.S.; Choi, C.W.; Ko, Y.H. Peripheral T cell lymphoma of the nasopharynx with expansion of EBV-positive B cells masquerading as an extranodal NK/T cell lymphoma, nasal type. Virchows. Arch. 2022, 481, 125–129. [Google Scholar] [CrossRef] [PubMed]
  105. Theurich, S.; Schlaak, M.; Steguweit, H.; Heukamp, L.C.; Wennhold, K.; Kurschat, P.; Rabenhorst, A.; Hartmann, K.; Schlösser, H.; Shimabukuro-Vornhagen, A.; et al. Targeting Tumor-Infiltrating B Cells in Cutaneous T-Cell Lymphoma. J. Clin. Oncol. 2016, 34, e110–e116. [Google Scholar] [CrossRef]
  106. Chen, M.M.; Zeng, G.P.; Li, J.; Fu, J.H.; Long, Y.Y.; Pan, J.Y.; Wei, L.Z.; Guan, J.Y.; Lin, Y.X.; You, H.; et al. High infiltration of CD20+ B lymphocytes in extranodal natural killer/T-cell lymphoma is associated with better prognosis. Br. J. Haematol. 2020, 191, e116–e120. [Google Scholar] [CrossRef]
  107. Shojaie, S.; Leibel, S.; Post, M. 5—The Extracellular Matrix in Development, Fetal and Neonatal Physiology, 5th ed.; Elsevier: Amsterdam, The Netherlands, 2017; pp. 49–54.e2. [Google Scholar]
  108. James, M.; Crawford, A.; Burt, D. Anatomy, Pathophysiology and Basic Mechanisms of Disease. MacSween’s Pathology of the Liver, 6th ed.; Churchill Livingstone: London, UK, 2012; pp. 1–77. ISBN 9780702033988. [Google Scholar]
  109. Wang, K.; Meng, X.; Guo, Z. Elastin Structure, Synthesis, Regulatory Mechanism and Relationship With Cardiovascular Diseases. Front. Cell Dev. Biol. 2021, 30, 596702. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  110. Dzobo, K.; Dandara, C. The Extracellular Matrix: Its Composition, Function, Remodeling, and Role in Tumorigenesis. Biomimetics 2023, 8, 146. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  111. Spada, S.; Tocci, A.; Di Modugno, F.; Nisticò, P. Fibronectin as a multiregulatory molecule crucial in tumor matrisome: From structural and functional features to clinical practice in oncology. J. Exp. Clin. Cancer Res. 2021, 40, 102. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  112. Verma, R.P.; Hansch, C. Matrix metalloproteinases (MMPs): Chemical-biological functions and (Q)SARs. Bioorg. Med. Chem. 2007, 15, 2223–2268. [Google Scholar] [CrossRef] [PubMed]
  113. Laronha, H.; Caldeira, J. Structure and Function of Human Matrix Metalloproteinases. Cells 2020, 9, 1076. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  114. Lagarrigue, F.; Dupuis-Coronas, S.; Ramel, D.; Delsol, G.; Tronchère, H.; Payrastre, B.; Gaits-Iacovoni, F. Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion. Cancer Res. 2010, 70, 6978–6987. [Google Scholar] [CrossRef] [PubMed]
  115. Van Lint, P.; Libert, C. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J. Leucoc. Biol. 2007, 82, 1375–1381. [Google Scholar] [CrossRef]
  116. Rømer, A.M.A.; Thorseth, M.L.; Madsen, D.H. Immune Modulatory Properties of Collagen in Cancer. Front. Immunol. 2021, 12, 791453. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  117. Rygiel, T.P.; Stolte, E.H.; de Ruiter, T.; van de Weijer, M.L.; Meyaard, L. Tumor-expressed collagens can modulate immune cell function through the inhibitory collagen receptor LAIR. Mol. Immunol. 2011, 49, 402–406. [Google Scholar] [CrossRef]
  118. Huang, J.; Zhang, L.; Wan, D.; Zhou, L.; Zheng, S.; Lin, S.; Qiao, Y. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct. Target Ther. 2021, 6, 153. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  119. Prakash, J.; Shaked, Y. The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics. Cancer Discov. 2024, 14, 1375–1388. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  120. Gao, L.; Li, H.; Jian, Q.-J.; Zhang, W.; Zhao, S.; Wang, K.; Liu, W. Comparative Analysis of Clinicopathological Features and Genetic Landscape of Relapsed/Refractory and Effectively Treated Extranodal Nasal NK/T Cell Lymphoma. Blood 2021, 138 (Suppl. 1), 1384. [Google Scholar] [CrossRef]
  121. Petkovic, I.; Stojnev, S.; Popovic, A.; Krstic, M.; Pejcic, I. Extranodal NK/T-cell lymphoma, nasal type overlapping aggressive NK-cell leukemia in course of progression. UHOD-Uluslar. Hematol. 2020, 30, 248–251. [Google Scholar] [CrossRef]
  122. Wang, J.P.; Hielscher, A. Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting. J. Cancer 2017, 8, 674–682. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  123. Schliemann, C.; Palumbo, A.; Zuberbühler, K.; Villa, A.; Kaspar, M.; Trachsel, E.; Klapper, W.; Menssen, H.D.; Neri, D. Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL. Blood 2009, 113, 2275–2283. [Google Scholar] [CrossRef] [PubMed]
  124. Hiserodt, J.C.; Laybourn, K.A.; Varani, J. Laminin inhibits the recognition of tumor target cells by murine natural killer (NK) and natural cytotoxic (NC) lymphocytes. Am. J. Pathol. 1985, 121, 148. [Google Scholar] [PubMed] [PubMed Central]
  125. Siegel, S.; Wagner, A.; Kabelitz, D.; Marget, M.; Coggin, J., Jr.; Barsoum, A.; Rohrer, J.; Schmitz, N.; Zeis, M. Induction of cytotoxic T-cell responses against the oncofetal antigen-immature laminin receptor for the treatment of hematologic malignancies. Blood 2003, 102, 4416–4423. [Google Scholar] [CrossRef] [PubMed]
  126. Pesapane, A.; Ragno, P.; Selleri, C.; Montuori, N. Recent Advances in the Function of the 67 kDa Laminin Receptor and its Targeting for Personalized Therapy in Cancer. Curr. Pharm. Des. 2017, 23, 4745–4757. [Google Scholar] [CrossRef] [PubMed]
  127. Brellier, F.; Chiquet-Ehrismann, R. How do tenascins influence the birth and life of a malignant cell? J. Cell Mol. Med. 2012, 16, 32–40. [Google Scholar] [CrossRef]
  128. Gritti, G.; Gianatti, A.; Petronzelli, F.; Boschini, C.; Rossi, R.; Trezzi, R.; Rossi, A.; Barbui, A.M.; Rambaldi, A. Tenascin-C Is Highly Expressed in T-Cell Non-Hodgkin Lymphomas and Represents an Attractive Target for Radioimmunotherapy. Blood 2016, 128, 4141. [Google Scholar] [CrossRef]
  129. Jahkola, T.; Toivonen, T.; Nordling, S.; von Smitten, K.; Virtanen, I. Expression of tenascin-C in intraductal carcinoma of human breast: Relationship to invasion. Eur. J. Cancer 1998, 34, 1687–1692. [Google Scholar] [CrossRef]
  130. Ghert, M.A.; Qi, W.N.; Erickson, H.P.; Block, J.A.; Scully, S.P. Tenascin-C splice variant adhesive/anti-adhesive effects on chondrosarcoma cell attachment to fibronectin. Cell Struct. Funct. 2001, 26, 179–187. [Google Scholar] [CrossRef] [PubMed]
  131. Zagzag, D.; Capo, V. Angiogenesis in the central nervous system: A role for vascular endothelial growth factor/vascular permeability factor and tenascin-C. Common molecular effectors in cerebral neoplastic and non-neoplastic “angiogenic diseases”. Histol. Histopathol. 2002, 17, 301–321. [Google Scholar] [PubMed]
  132. Puente Navazo, M.D.; Valmori, D.; Ruegg, C. The alternatively spliced domain TnFnIII A1A2 of the extracellular matrix protein tenascin-C suppresses activation-induced T lymphocyte proliferation and cytokine production. J. Immunol. 2001, 167, 6431–6440. [Google Scholar] [CrossRef]
  133. Cardesa-Salzmann, T.M.; Colomo, L.; Gutierrez, G.; Chan, W.C.; Weisenburger, D.; Climent, F.; Gonzalez-Barca, E.; Mercadal, S.; Arenillas, L.; Serrano, S.; et al. High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy. Haematologica 2011, 96, 996–1001. [Google Scholar] [CrossRef]
  134. Gritti, G.; Gianatti, A.; Petronzelli, F.; De Santis, R.; Pavoni, C.; Rossi, R.L.; Cattaneo, L.; Spagnoli, L.G.; Ferrari, S.; Rossi, A.; et al. Evaluation of tenascin-C by tenatumomab in T-cell non-Hodgkin lymphomas identifies a new target for radioimmunotherapy. Oncotarget 2018, 9, 9766–9775, Erratum in Oncotarget 2018, 9, 17256. [Google Scholar] [CrossRef] [PubMed]
  135. Fadnes, B.; Husebekk, A.; Svineng, G.; Rekdal, Ø.; Yanagishita, M.; Kolset, S.O.; Uhlin-Hansen, L. The proteoglycan repertoire of lymphoid cells. Glycoconj. J. 2012, 29, 513–523. [Google Scholar] [CrossRef] [PubMed]
  136. Chung, J.S.; Shiue, L.H.; Duvic, M.; Pandya, A.; Cruz, P.D.; Ariizumi, K., Jr. Sezary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-beta on the cell surface. Blood 2011, 117, 3382–3390. [Google Scholar] [CrossRef]
  137. Fujii, K.; Karpova, M.B.; Asagoe, K.; Georgiev, O.; Dummer, R.; Urosevic-Maiwald, M. Versican upregulation in Sézary cells alters growth, motility and resistance to chemotherapy. Leukemia 2015, 29, 2024–2032. [Google Scholar] [CrossRef]
  138. Borghini, N.; Lazzaretti, M.; Lunghi, P.; Malpeli, G.; Barbi, S.; Perris, R. A translational perspective of the malignant hematopoietic proteoglycome. Cell Biosci. 2025, 15, 25. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  139. Deb, G.; Cicala, A.; Papadas, A.; Asimakopoulos, F. Matrix proteoglycans in tumor inflammation and immunity. Am. J. Physiol. Cell Physiol. 2022, 323, C678–C693. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  140. Sakata, K.; Someya, M.; Omatsu, M.; Asanuma, H.; Hasegawa, T.; Ichimiya, S.; Hareyama, M.; Himi, T. The enhanced expression of the matrix metalloproteinase 9 in nasal NK/T-cell lymphoma. BMC Cancer 2007, 7, 229, Erratum in BMC Cancer 2018, 8, 45. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  141. Harabuchi, Y.; Takahara, M.; Kishibe, K.; Nagato, T.; Kumai, T. Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Basic Science and Clinical Progress. Front. Pediatr. 2019, 7, 141. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  142. Cheung, M.M.; Chan, J.K.; Lau, W.H.; Ngan, R.K.; Foo, W.W. Early stage nasal NK/T-cell lymphoma: Clinical outcome, prognostic factors, and the effect of treatment modality. Int. J. Radiat. Oncol. Biol. Phys. 2002, 54, 182–190. [Google Scholar] [CrossRef] [PubMed]
  143. Feng, Y.; Wu, L.; Sun, J.; Xiao, Q.; Feng, Z.; Li, J. Expression and Significance of MMP-26, TIMP-4 and MMP-9 in Extranodal Natural Killer (NK)/T-cell Lymphoma, Nasal type (ENKTCL) Lymphoma Cells. Cancer Res. Prev. Treat. Cancer 2014, 41, 269–273. [Google Scholar]
  144. Meneses-García, A.; Betancourt, A.M.; Abarca, J.H.; Montes, A.B.; Roa, L.S.; Ruíz-Godoy, L. Expression of the metalloproteases MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, TIMP-1 and TIMP-2 in angiocentric midfacial lymphomas. World J. Surg. Oncol. 2008, 6, 114. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  145. Provenzano, P.P.; Eliceiri, K.W.; Campbell, J.M.; Inman, D.R.; White, J.G.; Keely, P.J. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006, 4, 38. [Google Scholar] [CrossRef]
  146. Bhowmick, N.A.; Neilson, E.G.; Moses, H.L. Stromal fibroblasts in cancer initiation and progression. Nature 2004, 432, 332–337. [Google Scholar] [CrossRef] [PubMed]
  147. Lu, P.; Weaver, V.M.; Werb, Z. The extracellular matrix: A dynamic niche in cancer progression. J. Cell Biol. 2012, 196, 395–406. [Google Scholar] [CrossRef]
  148. Löffek, S.; Schilling, O.; Franzke, C.W. Series “matrix metalloproteinases in lung health and disease”: Biological role of matrix metalloproteinases: A critical balance. Eur. Respir. J. 2011, 38, 191–208. [Google Scholar] [CrossRef]
  149. Xu, B.; Wang, T. Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes. Tumour Biol. 2017, 39, 1010428317706227. [Google Scholar] [CrossRef] [PubMed]
  150. Mohseni, A.; Salehi, F.; Rostami, S.; Hadiloo, K.; Hashemi, M.; Baridjavadi, Z.; Ahangari, F.; Karami, N.; Samani, F.; Tahmasebi, S.; et al. Harnessing the power of exosomes for diagnosis, prognosis, and treatment of hematological malignancies. Stem Cell Res. Ther. 2025, 16, 6. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  151. Wang, X.; Huang, J.; Chen, W.; Li, G.; Li, Z.; Lei, J. The updated role of exosomal proteins in the diagnosis, prognosis, and treatment of cancer. Exp. Mol. Med. 2022, 54, 1390–1400. [Google Scholar] [CrossRef]
  152. Navarro-Tableros, V.; Gomez, Y.; Camussi, G.; Brizzi, M.F. Extracellular Vesicles: New Players in Lymphomas. Int. J. Mol. Sci. 2018, 20, 41. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  153. Boyiadzis, M.; Whiteside, T.L. The emerging roles of tumor-derived exosomes in hematological malignancies. Leukemia 2017, 31, 1259–1268. [Google Scholar] [CrossRef]
  154. Chen, W.; Xie, Y.; Li, F.; Wen, P.; Wang, L. EBV + B cell-derived exosomes promote EBV-associated T/NK-cell lymphoproliferative disease immune evasion by STAT3/IL-10/PD-L1 pathway. Immunol. Res. 2024, 72, 1327–1336. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  155. Rutherford, S.C.; Fachel, A.A.; Li, S.; Sawh, S.; Muley, A.; Ishii, J.; Saxena, A.; Dominguez, P.M.; Caldas Lopes, E.; Agirre, X.; et al. Extracellular vesicles in DLBCL provide abundant clues to aberrant transcriptional programming and genomic alterations. Blood 2018, 132, e13–e23. [Google Scholar] [CrossRef] [PubMed]
  156. Feng, Y.; Zhong, M.; Zeng, S.; Wang, L.; Liu, P.; Xiao, X.; Liu, Y. Exosome-derived miRNAs as predictive biomarkers for diffuse large B-cell lymphoma chemotherapy resistance. Epigenomics 2018, 11, 35–51. [Google Scholar] [CrossRef] [PubMed]
  157. Li, J.; Tian, T.; Zhou, X. The role of exosomal shuttle RNA (esRNA) in lymphoma. Crit. Rev. Oncol. Hematol. 2019, 137, 27–34. [Google Scholar] [CrossRef]
  158. Kataoka, K.; Miyoshi, H.; Sakata, S.; Dobashi, A.; Couronne, L.; Kogure, Y.; Sato, Y.; Nishida, K.; Gion, Y.; Shiraishi, Y.; et al. Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. Leukemia 2019, 33, 1687–1699. [Google Scholar] [CrossRef] [PubMed]
  159. Li, J.W.; Wei, P.; Guo, Y.; Shi, D.; Yu, B.H.; Su, Y.F.; Li, X.Q.; Zhou, X.Y. Clinical significance of circulating exosomal PD-L1 and soluble PD-L1 in extranodal NK/T-cell lymphoma, nasal-type. Am. J. Cancer Res. 2020, 10, 4498. [Google Scholar] [PubMed] [PubMed Central]
  160. Smith, N.A.; Coleman, C.B.; Gewurz, B.E.; Rochford, R. CD21 (Complement Receptor 2) Is the Receptor for Epstein-Barr Virus Entry into T Cells. J. Virol. 2020, 94, e00428-20. [Google Scholar] [CrossRef]
  161. Kimura, H. EBV in T-/NK-cell tumorigenesis. Adv. Exp. Med. Biol. 2018, 1045, 459–475. [Google Scholar]
  162. Kimura, H.; de Leval, L.; Cai, Q.; Kim, W.S. EBV-associated NK and T-cell lymphoid neoplasms. Curr. Opin. Oncol. 2022, 34, 422–431. [Google Scholar] [CrossRef]
  163. Xiong, J.; Dai, Y.T.; Wang, W.F.; Zhang, H.; Wang, C.F.; Yin, T.; Cheng, S.; Zhong, H.J.; Yu, S.H.; Jiang, L.; et al. GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis. Sci. Bull. 2023, 68, 2607–2619. [Google Scholar] [CrossRef]
  164. Proietti, F.A.; Carneiro-Proietti, A.B.; Catalan-Soares, B.C.; Murphy, E.L. Global epidemiology of HTLV-I infection and associated diseases. Oncogene 2005, 24, 6058–6068. [Google Scholar] [CrossRef] [PubMed]
  165. Gonçalves, D.U.; Proietti, F.A.; Ribas, J.G.; Araújo, M.G.; Pinheiro, S.R.; Guedes, A.C.; Carneiro-Proietti, A.B. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin. Microbiol. Rev. 2010, 23, 577–589. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  166. Mohanty, S.; Harhaj, E.W. Mechanisms of Oncogenesis by HTLV-1 Tax. Pathogens 2020, 9, 543. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  167. Currer, R.; Van Duyne, R.; Jaworski, E.; Guendel, I.; Sampey, G.; Das, R.; Narayanan, A.; Kashanchi, F. HTLV tax: A fascinating multifunctional co-regulator of viral and cellular pathways. Front. Microbiol. 2012, 3, 406. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  168. Takeuchi, M.; Miyoshi, H.; Ohshima, K. Tumor microenvironment of adult T-cell leukemia/lymphoma. J. Clin. Exp. Hematop. 2021, 61, 202–209. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  169. Nakahata, S.; Enriquez-Vera, D.; Jahan, M.I.; Sugata, K.; Satou, Y. Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review. Biomolecules 2023, 13, 1543. [Google Scholar] [CrossRef] [PubMed]
  170. Kataoka, K.; Nagata, Y.; Kitanaka, A.; Shiraishi, Y.; Shimamura, T.; Yasunaga, J.; Totoki, Y.; Chiba, K.; Sato-Otsubo, A.; Nagae, G.; et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat. Genet. 2015, 47, 1304–1315. [Google Scholar] [CrossRef]
  171. Asano, N.; Miyoshi, H.; Kato, T.; Shimono, J.; Yoshida, N.; Kurita, D.; Sasaki, Y.; Kawamoto, K.; Ohshima, K.; Seto, M. Expression pattern of immunosurveillance-related antigen in adult T cell leukaemia/lymphoma. Histopathology 2018, 72, 945–954. [Google Scholar] [CrossRef]
  172. Holling, T.M.; Schooten, E.; Langerak, A.W.; van den Elsen, P.J. Regulation of MHC class II expression in human T-cell malignancies. Blood 2004, 103, 1438–1444. [Google Scholar] [CrossRef]
  173. Shirono, K.; Hattori, T.; Hata, H.; Nishimura, H.; Takatsuki, K. Profiles of expression of activated cell antigens on peripheral blood and lymph node cells from different clinical stages of adult T-cell leukemia. Blood 1989, 73, 1664–1671. [Google Scholar] [CrossRef]
  174. Takeuchi, M.; Miyoshi, H.; Asano, N.; Yoshida, N.; Yamada, K.; Yanagida, E. Human leukocyte antigen class II expression is a good prognostic factor in adult T-cell leukemia/lymphoma. Haematologica 2019, 104, 1626–1632. [Google Scholar] [CrossRef] [PubMed]
  175. Komohara, Y.; Niino, D.; Saito, Y.; Ohnishi, K.; Horlad, H.; Ohshima, K.; Takeya, M. Clinical significance of CD163⁺ tumor-associated macrophages in patients with adult T-cell leukemia/lymphoma. Cancer Sci. 2013, 104, 945–951. [Google Scholar] [CrossRef]
  176. Veillette, A.; Chen, J. SIRPα-CD47 Immune Checkpoint Blockade in Anticancer Therapy. Trends Immunol. 2018, 39, 173–184. [Google Scholar] [CrossRef] [PubMed]
  177. Yanagida, E.; Miyoshi, H.; Takeuchi, M.; Yoshida, N.; Nakashima, K.; Yamada, K.; Umeno, T.; Shimasaki, Y.; Furuta, T.; Seto, M. Clinicopathological analysis of immunohistochemical expression of CD47 and SIRPα in adult T-cell leukemia/lymphoma. Hematol. Oncol. 2020, 38, 680–688. [Google Scholar] [CrossRef]
  178. Miyoshi, H.; Kiyasu, J.; Kato, T.; Yoshida, N.; Shimono, J.; Yokoyama, S.; Taniguchi, H.; Sasaki, Y.; Kurita, D.; Kawamoto, K.; et al. PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma. Blood 2016, 128, 1374–1381. [Google Scholar] [CrossRef]
  179. Azakami, K.; Sato, T.; Araya, N.; Utsunomiya, A.; Kubota, R.; Suzuki, K.; Hasegawa, D.; Izumi, T.; Fujita, H.; Aratani, S.; et al. Severe loss of invariant NKT cells exhibiting anti-HTLV-1 activity in patients with HTLV-1-associated disorders. Blood 2009, 114, 3208–3215. [Google Scholar] [CrossRef]
  180. Koya, J.; Saito, Y.; Kameda, T.; Kogure, Y.; Yuasa, M.; Nagasaki, J.; McClure, M.B.; Shingaki, S.; Tabata, M.; Tahira, Y.; et al. Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV. Blood Cancer Discov. 2021, 2, 450–467. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  181. Wang, H.; Fu, B.-B.; Gale, R.P.; Liang, Y. NK-/T-cell lymphomas. Leukemia 2021, 35, 2460–2468. [Google Scholar] [CrossRef]
  182. Koo, G.C.; Tan, S.Y.; Tang, T.; Poon, S.L.; Allen, G.E.; Tan, L.; Chong, S.C.; Ong, W.S.; Tay, K.; Tao, M.; et al. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov. 2012, 2, 591–597. [Google Scholar] [CrossRef]
  183. Fochi, S.; Mutascio, S.; Bertazzoni, U.; Zipeto, D.; Romanelli, M.G. HTLV Deregulation of the NF-κB Pathway: An Update on Tax and Antisense Proteins Role. Front. Microbiol. 2018, 9, 285. [Google Scholar] [CrossRef] [PubMed]
  184. Daver, N.; McClain, K.; Allen, C.E.; Parikh, S.A.; Otrock, Z.; Rojas-Hernandez, C.; Blechacz, B.; Wang, S.; Minkov, M.; Jordan, M.B.; et al. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer 2017, 123, 3229–3240. [Google Scholar] [CrossRef]
  185. Knauft, J.; Schenk, T.; Ernst, T.; Schnetzke, U.; Hochhaus, A.; La Rosée, P.; Birndt, S. Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH): A scoping review unveils clinical and diagnostic patterns of a lymphoma subgroup with poor prognosis. Leukemia 2024, 38, 235–249. [Google Scholar] [CrossRef]
  186. Semenzato, G.; Teramo, A.; Barilà, G.; Calabretto, G.; Rampazzo, E.; Buson, E.; Zambello, R. NK-type large granular lymphocyte leukemia comes of age. HemaSphere 2025, 9, e70161. [Google Scholar] [CrossRef] [PubMed]
  187. Calabretto, G.; Teramo, A.; Barilà, G.; Vicenzetto, C.; Gasparini, V.R.; Semenzato, G.; Zambello, R. Neutropenia and Large Granular Lymphocyte Leukemia: From Pathogenesis to Therapeutic Options. Cells 2021, 10, 2800. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  188. Orland, M.; Ogbue, O.; Dima, D.; Omar, N.; Mustafa Ali, M.K. Large granular lymphocytic leukemia: Clinical features, molecular pathogenesis, diagnosis and treatment. Cancers 2024, 16, 1307. [Google Scholar] [CrossRef]
  189. Lamy, T.; Moignet, A.; Loughran, T.P., Jr. LGL leukemia: From pathogenesis to treatment. Blood 2017, 129, 1082–1094. [Google Scholar] [CrossRef] [PubMed]
  190. Teramo, A.; Barilà, G.; Calabretto, G.; Vicenzetto, C.; Gasparini, V.R.; Semenzato, G.; Zambello, R. Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia. Front. Oncol. 2020, 10, 152. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  191. Zhang, R.; Shah, M.V.; Loughran, T.P., Jr. The root of many evils: Indolent large granular lymphocyte leukaemia and associated disorders. Hematol. Oncol. 2010, 28, 105–117. [Google Scholar] [CrossRef]
  192. Kiel, M.J.; Velusamy, T.; Rolland, D.; Sahasrabuddhe, A.A.; Chung, F.; Bailey, N.G.; Schrader, A.; Li, B.; Li, J.Z.; Ozel, A.B.; et al. Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood 2014, 124, 1460–1472. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  193. Wahnschaffe, L.; Braun, T.; Timonen, S.; Giri, A.K.; Schrader, A.; Wagle, P.; Almusa, H.; Johansson, P.; Bellanger, D.; López, C.; et al. JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL. Cancers 2019, 11, 1833. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  194. El Hussein, S.; Medeiros, L.J.; Khoury, J.D. Aggressive NK Cell Leukemia: Current State of the Art. Cancers 2020, 12, 2900. [Google Scholar] [CrossRef]
  195. Zhao, A.; Yang, J.; Li, M.; Li, L.; Gan, X.; Wang, J.; Li, H.; Shen, K.; Yang, Y.; Niu, T. Epstein-Barr Virus-Positive Lymphoma-Associated Hemophagocytic Syndrome: A Retrospective, Single-Center Study of 51 Patients. Front. Immunol. 2022, 13, 882589. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  196. Watanabe, T. Adult T-cell leukemia: Molecular basis for clonal expansion and transformation of HTLV-1–infected T cells. Blood 2017, 129, 1071–1081. [Google Scholar] [CrossRef]
  197. Sawada, L.; Nagano, Y.; Hasegawa, A.; Kanai, H.; Nogami, K.; Ito, S.; Sato, T.; Yamano, Y.; Tanaka, Y.; Masuda, T.; et al. IL-10-mediated signals act as a switch for lymphoproliferation in Human T-cell leukemia virus type-1 infection by activating the STAT3 and IRF4 pathways. PLoS Pathog. 2017, 13, e1006597. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  198. Marques-Piubelli, M.L.; Amador, C.; Vega, F. Pathologic and molecular insights in nodal T-follicular helper cell lymphomas. Front. Oncol. 2023, 13, 1105651. [Google Scholar] [CrossRef] [PubMed]
  199. Chiba, S.; Sakata-Yanagimoto, M. Advances in understanding of angioimmunoblastic T-cell lymphoma. Leukemia 2020, 34, 2592–2606. [Google Scholar] [CrossRef]
  200. Lage, L.A.d.P.C.; Culler, H.F.; Reichert, C.O.; da Siqueira, S.A.C.; Pereira, J. Angioimmunoblastic T-cell lymphoma and correlated neoplasms with TFH phenotype: From molecular mechanisms to therapeutic advances. Front. Oncol. 2023, 13, 1177590. [Google Scholar] [CrossRef]
  201. Amador, C.; Chan, W.C. Nodal peripheral T-cell lymphomas in the new classification systems. Cancer Biol. Med. 2024, 20, 922–926. [Google Scholar] [CrossRef] [PubMed]
  202. Iqbal, J.; Wright, G.; Wang, C.; Rosenwald, A.; Gascoyne, R.D.; Weisenburger, D.D.; Greiner, T.C.; Smith, L.; Guo, S.; Wilcox, R.A.; et al. Lymphoma Leukemia Molecular Profiling Project and the International Peripheral T-cell Lymphoma Project. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 2014, 123, 2915–2923. [Google Scholar] [CrossRef]
  203. Miyawaki, K.; Sugio, T. Lymphoma Microenvironment in DLBCL and PTCL-NOS: The key to uncovering heterogeneity and the potential for stratification. J. Clin. Exp. Hematop. 2022, 62, 127–135. [Google Scholar] [CrossRef] [PubMed]
  204. Sugio, T.; Miyawaki, K.; Kato, K.; Sasaki, K.; Yamada, K.; Iqbal, J.; Miyamoto, T.; Ohshima, K.; Maeda, T.; Miyoshi, H.; et al. Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS. Blood Adv. 2018, 2, 2242–2252. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  205. Chiarle, R.; Simmons, W.J.; Cai, H.; Dhall, G.; Zamo, A.; Raz, R.; Karras, J.G.; Levy, D.E.; Inghirami, G. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat. Med. 2005, 11, 623–629. [Google Scholar] [CrossRef]
  206. Kasprzycka, M.; Marzec, M.; Liu, X.; Zhang, Q.; Wasik, M.A. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT. Proc. Natl. Acad. Sci. USA 2006, 103, 9964–9969. [Google Scholar] [CrossRef] [PubMed]
  207. Marzec, M.; Zhang, Q.; Goradia, A.; Raghunath, P.N.; Liu, X.; Paessler, M.; Wang, H.Y.; Wysocka, M.; Cheng, M.; Ruggeri, B.A.; et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc. Natl. Acad. Sci. USA 2008, 105, 20852–20857. [Google Scholar] [CrossRef]
  208. Crescenzo, R.; Abate, F.; Lasorsa, E.; Tabbo’, F.; Gaudiano, M.; Chiesa, N.; Di Giacomo, F.; Spaccarotella, E.; Barbarossa, L.; Ercole, E.; et al. T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies”. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 2015, 27, 516–532, Erratum in Cancer Cell 2015, 27, 516–532. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  209. Boddicker, R.L.; Kip, N.S.; Xing, X.; Zeng, Y.; Yang, Z.Z.; Lee, J.H.; Almada, L.L.; Elsawa, S.F.; Knudson, R.A.; Law, M.E.; et al. The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma. Blood 2015, 125, 3118–3127. [Google Scholar] [CrossRef]
  210. Virmani, P.; Jawed, S.; Myskowski, P.L.; Horwitz, S.; Skripnik Lucas, A.; Moskowitz, A.; Pulitzer, M.; Zain, J.; Rosen, S.T.; Querfeld, C. Long-term follow-up and management of small and medium-sized CD4+ T cell lymphoma and CD8+ lymphoid proliferations of acral sites: A multicenter experience. Int. J. Dermatol. 2016, 55, 1248–1254. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  211. Fujii, K. New Therapies and Immunological Findings in Cutaneous T-Cell Lymphoma. Front. Oncol. 2018, 8, 198. [Google Scholar] [CrossRef]
  212. Marques-Piubelli, M.L.; Miranda, R.N. What’s new in hematopathology 2023: Updates on mature T-cell neoplasms in the 5th edition of the WHO classification. J. Pathol. Transl. Med. 2023, 57, 246–249. [Google Scholar] [CrossRef]
  213. Stephan, C.; Grossman, M.E.; Magro, C.M. Primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder: A clinical and histologic retrospective cohort study. Clin. Dermatol. 2023, 41, 666–679. [Google Scholar] [CrossRef]
  214. Al-Toma, A.; Verbeek, W.H.; Hadithi, M.; von Blomberg, B.M.; Mulder, C.J. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: Retrospective evaluation of single-centre experience. Gut 2007, 56, 1373–1378. [Google Scholar] [CrossRef]
  215. Cording, S.; Lhermitte, L.; Malamut, G.; Berrabah, S.; Trinquand, A.; Guegan, N.; Villarese, P.; Kaltenbach, S.; Meresse, B.; Khater, S.; et al. Oncogenetic landscape of lymphomagenesis in coeliac disease. Gut 2022, 71, 497–508. [Google Scholar] [CrossRef]
  216. Veloza, L.; Cavalieri, D.; Missiaglia, E.; Ledoux-Pilon, A.; Bisig, B.; Pereira, B.; Bonnet, C.; Poullot, E.; Quintanilla-Martinez, L.; Dubois, R.; et al. Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome. Haematologica 2023, 108, 181–195. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  217. Xia, D.; Morgan, E.A.; Berger, D.; Pinkus, G.S.; Ferry, J.A.; Zukerberg, L.R. NK-Cell Enteropathy and Similar Indolent Lymphoproliferative Disorders: A Case Series with Literature Review. Am. J. Clin. Pathol. 2019, 151, 75–85. [Google Scholar] [CrossRef] [PubMed]
  218. Li, W. The 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors. In Leukemia [Internet]; Li, W., Ed.; Exon Publications: Brisbane, AU, USA, 2022. [Google Scholar] [PubMed]
  219. Bao, C.; Zhou, D.; Zhu, L.; Qian, W.; Ye, X. Increased serum level of interleukin-6 correlates with negative prognostic factors in extranodal NK/T-cell lymphoma. Transl. Cancer Res. 2020, 9, 2378–2389. [Google Scholar] [CrossRef] [PubMed]
  220. Wang, H.; Wang, L.; Wuxiao, Z.; Huang, H.; Jiang, W.; Li, Z.; Lu, Y.; Xia, Z. Increased serum levels of interleukin-10 predict poor prognosis in extranodal natural killer/T-cell lymphoma patients receiving asparaginase-based chemotherapy. Oncol. Targets Ther. 2015, 8, 2589–2599. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  221. Kim, S.J.; Hong, M.; Do, I.G.; Lee, S.H.; Ryu, K.J.; Yoo, H.Y.; Hong, J.Y.; Ko, Y.H.; Kim, W.S. Serum survivin and vascular endothelial growth factor in extranodal NK/T-cell lymphoma, nasal type: Implications for a potential new prognostic indicator. Haematologica 2015, 100, e106–e109. [Google Scholar] [CrossRef]
  222. Glover, A.; Shannon-Lowe, C. From pathobiology to targeted treatment in Epstein-Barr virus–related T-cell and NK-cell lymphoproliferative diseases. Ann. Lymphoma 2021, 5, 31. [Google Scholar] [CrossRef]
  223. Cohen, J.I.; Manoli, I.; Dowdell, K.; Krogmann, T.A.; Tamura, D.; Radecki, P.; Bu, W.; Turk, S.P.; Liepshutz, K.; Hornung, R.L.; et al. Hydroa vacciniforme-like lymphoproliferative disorder: An EBV disease with a low risk of systemic illness in whites. Blood 2019, 133, 2753–2764. [Google Scholar] [CrossRef] [PubMed]
  224. Kim, W.Y.; Montes-Mojarro, I.A.; Fend, F.; Quintanilla-Martinez, L. Epstein–Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases. Front. Pediatr. 2019, 7, 71. [Google Scholar] [CrossRef] [PubMed]
  225. Arai, A.; Nogami, A.; Imadome, K.; Kurata, M.; Murakami, N.; Fujiwara, S.; Miura, O. Sequential monitoring of serum IL-6, TNF-α, and IFN-γ levels in a CAEBV patient treated by plasma exchange and immunochemotherapy. Int. J. Hematol. 2012, 96, 669–673, Erratum in Int. J. Hematol. 2013, 97, 301. [Google Scholar] [CrossRef] [PubMed]
  226. Ohga, S.; Nomura, A.; Takada, H.; Tanaka, T.; Furuno, K.; Takahata, Y.; Kinukawa, N.; Fukushima, N.; Imai, S.; Hara, T. Dominant expression of interleukin-10 and transforming growth factor-beta genes in activated T-cells of chronic active Epstein-Barr virus infection. J. Med. Virol. 2004, 74, 449–458. [Google Scholar] [CrossRef] [PubMed]
  227. Marsh, R.A.; Allen, C.E.; McClain, K.L. Epstein–Barr Virus and Hemophagocytic Lymphohistiocytosis. Front. Immunol. 2017, 8, 1902. [Google Scholar] [CrossRef]
  228. Cvetković, Z.; Marković, O.; Marinković, G.; Pejić, S.; Vučić, V. Tumor Microenvironment, Inflammation, and Inflammatory Prognostic Indices in Diffuse Large B-Cell Lymphomas: A Narrative Review. Int. J. Mol. Sci. 2025, 26, 5670. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
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