Search Results (668)

Classical Hodgkin lymphoma (cHL) is a paradigmatic example of a malignancy in which the tumor microenvironment (TME) plays a dominant role in disease biology. Malignant Hodgkin and Reed–Sternberg (HRS) cells typically constitute only a small minority of the tumor mass (approximately 1–5%). HRS cells are embedded within a complex, highly structured immune and stromal milieu that drives survival, immune evasion, and therapy response. Over the past decade, transcriptomic approaches, particularly single-cell RNA sequencing, have reshaped our understanding of cellular heterogeneity within cHL. However, these approaches lack spatial context, a limitation that is especially relevant in cHL, where cell–cell interactions and physical proximity are central to immune evasion and tumor support. Recent advances in spatial transcriptomics now enable genome-scale, spatially resolved interrogation of gene expression in situ. In this review, we summarize spatially resolved studies of the cHL microenvironment, discuss what they reveal about HRS-centered cellular niches and immune evasion, and highlight how these findings may inform risk stratification, biomarker discovery and microenvironment-directed therapies. Full article

Background/Objectives: MSS-CRC comprises a heterogeneous group of tumors generally considered “immune cold” due to limited neoantigen generation and T-cell exclusion or inactivation. Current evidence indicates that the composition of T and B immune cells within the tumor microenvironment represents a prognostically relevant factor, significantly associated with both tumor expression profiles and molecular subtypes. Methods: We conducted an exploratory analysis to identify prognostically relevant immune cell components in this group of tumors and to investigate corresponding differences in RNA-based bulk expression and high-resolution spatial transcriptomic profiles. Results: A total of 254 localized mismatch repair-proficient colorectal cancer cases were evaluated. Our findings revealed PD-L1 expression as a robust independent prognostic biomarker associated with favorable outcomes in this specific population. Bulk RNA expression analysis showed that PD-L1-negative tumors exhibited an expression profile consistent with abundant cancer-associated fibroblast infiltration, increased matrix stiffness, and impaired immune activation—features consistent with tumor progression and poorer clinical outcomes. In contrast, PD-L1-positive tumors displayed stromal programs enriched in immune activation and controlled remodeling, consistent with an immunologically active microenvironment. Spatial transcriptomics added an additional layer of evidence, revealing that epithelial to mesenchymal transition-related programs can dominate stromal niches in PD-L1-negative tumors, particularly within macrophage-enriched stromal regions. Conclusions: Our observations suggest an association between PD-L1 expression on immune cells and immune-activated versus mesenchymal-dominant states, potentially occurring within macrophage-enriched stromal niches. These results provide insight into the biological mechanisms underlying disease progression and highlight tumor-associated macrophages as a potential therapeutic target to overcome immune resistance, particularly in PD-L1-negative MSS-CRC tumors. Full article

Bone marrow(BM) is the primary site of hematopoiesis, supporting the self-renewal and differentiation of hematopoietic stem cells (HSCs). Its function depends on a highly complex microenvironment composed of stromal cells, vascular networks, extracellular matrix components, and dynamic biophysical signals. Traditional two-dimensional culture systems and animal models fail to adequately recapitulate the spatial architecture and dynamic regulatory processes of the human bone marrow niche, thereby limiting in-depth investigations into hematopoietic regulatory mechanisms, disease pathogenesis, and drug-induced bone marrow toxicity. In recent years, advances in microphysiological systems (MPS) have provided novel engineering approaches for the in vitro reconstruction of the bone marrow microenvironment. This review systematically summarizes current construction strategies for bone marrow MPS, including three-dimensional self-organized bone marrow organoids and microfluidic bone marrow-on-a-chip platforms. Particular attention is given to the roles of key cellular components, biomaterial scaffolds, vascularized architectures, and dynamic perfusion systems in biomimetic bone marrow engineering. In addition, we discuss strategies for constructing more complex models, such as vascular niches, vascularized bone tissue constructs, and bone metastasis models. Bone marrow MPS more faithfully recapitulate the hematopoietic microenvironment and provide a physiologically relevant in vitro platform for hematopoietic research, disease modeling, and drug evaluation, thereby supporting future advances in precision and regenerative medicine. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Despite effective antiretroviral therapy, HIV persists in diverse tissue reservoirs that pose major barriers to a cure. This review examines the heterogeneous maintenance mechanisms of HIV reservoirs in lymph nodes, intestinal mucosa, and the central nervous system (CNS). It analyzes how distinct tissue microenvironments—including immune-privileged niches, specialized cellular subsets, and local signaling networks—govern viral persistence and latency. Lymph nodes function as a dynamic hub interconnected with systemic reservoirs; the intestinal mucosa represents a site shaped by barrier integrity, microbial translocation, and mucosal immunity; the CNS constitutes a compartmentalized sanctuary protected by the blood–brain barrier. The review further discusses tissue-specific antiretroviral drug penetration and targeted clearance strategies, providing a foundation for developing multi-site intervention approaches toward HIV cure. Full article

Oocyte competency is a crucial determinant of fertilisation success and the initial development of embryos in assisted reproductive technologies. The metabolic and biochemical environment of the ovarian follicle is crucial for determining oocyte developmental potential, alongside genetic integrity. The follicular microenvironment includes a complex network of signalling chemicals that regulate mitochondrial activity, steroidogenesis, oxidative balance, and cellular energy metabolism. Recently, metabolic hormones originating from adipose tissue and skeletal muscle, namely, adipokines and myokines, have received considerable focus as crucial regulators of ovarian physiology. Adiponectin, irisin, and the recently identified hormone asprosin have emerged as crucial metabolic regulators influencing granulosa cell activity, mitochondrial bioenergetics, insulin signalling pathways, and redox homeostasis inside the follicular niche. Adiponectin mostly provides metabolic protection by activating AMP-activated protein kinase (AMPK) and improving insulin sensitivity, which in turn enhances mitochondrial efficiency and steroidogenic function in granulosa cells. Irisin, derived from the breakdown of fibronectin type III domain-containing protein 5 (FNDC5), aids the developing oocyte by facilitating mitochondrial biogenesis, augmenting oxidative phosphorylation, and altering cellular defence mechanisms against oxidative stress. Conversely, asprosin has been associated with glucogenic signalling, metabolic stress, and probable mitochondrial malfunction, suggesting a possible relationship between systemic metabolic problems and negative reproductive consequences. Clinical and experimental research indicate that the levels of these metabolic regulators in follicular fluid may correlate with ovarian response, oocyte quality, fertilisation rates, and embryo development during in vitro fertilisation cycles. This review consolidates current molecular, cellular, and clinical information, clarifying the pathways by which adipokines and myokines influence follicular metabolism and impact oocyte competency. Understanding the metabolic connections between systemic endocrine signals and the follicular milieu may provide novel indicators for reproductive prognosis and provide new treatment targets to improve assisted reproduction outcomes. Full article

Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of extranodal non-Hodgkin lymphomas. With the publication of the fifth edition of the World Health Organization Classification of Hematolymphoid Tumors, the diagnostic framework for CTCL has shifted from primarily morphologic phenotypes toward an emphasis on molecular drivers. Current research suggests that malignant clones may arise from somatic mutations at the hematopoietic stem cell stage and may follow a continuous hematogenous dissemination model with bidirectional trafficking between the skin and systemic circulation. At the molecular level, genomic instability, often associated with somatic copy-number variations, may promote activation of the janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway through gene-dosage effects. In parallel, chromatin remodeling linked to EZH2 overexpression and reduced special SATB1 expression may support a Th2-polarized program. This phenotype may contribute to epidermal barrier impairment via cytokines such as Interleukins-4 (IL-4) and IL-13, potentially creating conditions permissive for Staphylococcus aureus colonization. Microbial superantigens and exotoxins may further contribute to tumor progression and therapeutic resistance by reinforcing JAK/STAT signaling, particularly STAT3, and reducing CD8+ T-cell–mediated immune surveillance. In the dermis, reprogramming of cancer-associated fibroblasts and polarization of macrophages toward an M2 phenotype may collectively contribute to an immunosuppressive niche. Emerging biomarkers, including CD74, and acquired resistance mechanisms after anti-C-C chemokine receptor 4 therapy further extend the translational relevance of recent pathologic findings. Overall, CTCL evolution appears to be a systemic process shaped by interactions between tumor-intrinsic genetic alterations and the skin microenvironment. Full article

The impact of anesthetic technique on long-term oncologic outcomes remains controversial. While early observational data suggested that regional anesthesia might reduce cancer recurrence, large randomized trials have failed to demonstrate consistent survival benefits. This apparent contradiction may not reflect biological neutrality, but rather a mismatch between trial design and the inflammatory biology of the perioperative period. Surgical resection provokes an acute and intense inflammatory surge characterized by sympathetic activation, cytokine release, neutrophil extracellular trap formation, endothelial activation, and transient suppression of cellular immunity. During this perioperative inflammatory window, circulating tumor cells encounter a biologically permissive microenvironment that may facilitate immune evasion, adhesion, and early metastatic niche establishment. The magnitude of this inflammatory response varies across patients and may represent a critical, yet under-recognized, determinant of tumor–host dynamics. Anesthetic and analgesic strategies influence this inflammatory cascade. By attenuating nociceptive signaling and sympathetic activation, regional anesthesia may modulate perioperative immune and immunometabolic pathways. However, it should not be framed as an anti-cancer therapy per se, but rather as a potential regulator of the transient inflammatory milieu that shapes early oncologic biology. We propose that prior neutral trials may reflect methodological misalignment, including heterogeneous tumor populations, absence of inflammatory stratification, and reliance on distant survival endpoints without mechanistic correlates. Future investigations should integrate perioperative immune phenotyping, inflammatory biomarkers, and tumor subtype stratification to determine whether modulation of acute surgical inflammation meaningfully alters early tumor–host interactions. Reconceptualizing the perioperative period as a biologically active inflammatory interface may refine the anesthesiologist’s role within perioperative oncology and open new avenues for precision-based perioperative modulation. Full article

Prostate cancer is one of the most prevalent malignancies among men and remains a major clinical challenge due to the complex tumor microenvironment. Understanding gene expression dynamics at both cellular and spatial levels is essential for improving therapeutic strategies. In this study, we performed an integrated multi-omics analysis using single-cell RNA sequencing and spatial transcriptomics. scRNA-seq data from 15 prostate samples, including 8 normal and 7 tumor tissues, were analyzed to characterize distinct cellular populations. Spatial transcriptomic profiling was conducted on three FFPE prostate tissue sections, including adjacent normal tissue, acinar cell carcinoma, and invasive adenocarcinoma, using the standard 10x Genomics Visium FFPE platform (55 µm capture spots). Single-cell analysis revealed heterogeneity among epithelial, stromal, and immune cell populations, highlighting complex signaling networks in which myeloid cells may contribute to tumor progression through immune suppression and epithelial adaptability. Spatial transcriptomic analysis further identified region-specific expression patterns and spatially restricted tumor niches, including the regional establishment of TXNIP and BIRC3 as genes associated with metabolic stress and inflammatory survival pathways. The spatial colocalization of BIRC3 with tumor vasculature in invasive carcinoma tissue suggests a novel interaction. Our discoveries using an integrated single-cell and spatial transcriptomic approach reveal a high-resolution molecular map of prostate cancer with spatial features that may provide further therapeutic investigation. Full article

Despite the remarkable success of antiretroviral therapy (ART) in suppressing human immunodeficiency virus type 1 (HIV-1) replication, viral persistence remains a major barrier to cure. This persistence is sustained by heterogeneous cellular reservoirs in which viral expression is tightly regulated by host-dependent molecular mechanisms. Beyond the canonical cluster of differentiation 4 (CD4+) T-cell reservoirs, HIV-1 establishes long-lived infection in myeloid cells, glial populations within the central nervous system (CNS), and additional non-canonical cellular niches, each characterized by distinct transcriptional, epigenetic, and immune environments. In this review, we synthesize recent advances in understanding how HIV-1 expression, latency, and reactivation are shaped across diverse susceptible cell types. We highlight cell-type-specific mechanisms governing viral integration, chromatin organization, transcriptional elongation, innate immune sensing, host restriction factors, and cytoskeletal regulation. Particular emphasis is placed on how host signaling pathways and immune microenvironments contribute to reservoir stability and heterogeneity, complicating eradication strategies. We further discuss immunomodulatory approaches that seek to modulate viral expression without exacerbating immune activation. By integrating molecular, cellular, and immunological perspectives, this review provides a framework for understanding HIV-1 persistence as a context-dependent process and underscores the need for cell-type-tailored strategies in HIV cure research. Full article

Background: Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) exhibit substantial heterogeneity, reflecting the diversity of the germinal center (GC). Histologic transformation of FL to DLBCL is associated with poor prognosis, yet robust biomarkers predicting transformation remain limited. Methods: We integrated single-cell DNA sequencing, single-cell RNA sequencing, and spatial transcriptomics in diagnostic lymph-node biopsies from non-transformed FL (ntFL), transformed FL (tFL), and DLBCL to characterize clonal states and immune niches in GC lymphomas. T-cell signatures associated with transformation were evaluated in an independently published single-cell FL dataset. Results: Transcriptional profiling revealed similarities between tFL and DLBCL, consistent with a GC-related malignant program. The tFL microenvironment showed enrichment of exhausted CD4⁺ regulatory and CD8⁺ effector T cells, together with CD4⁺ follicular helper T cells (Tfh) displaying an adhesion-related phenotype. Spatial analysis suggested increased proximity of exhausted/immunosuppressive T cells and enhanced Tfh-B-cell interactions in tFL compared with ntFL. These immune signatures were also observed in an external cohort and were associated with early transformation. In addition, clonal hematopoiesis-associated mutations were detected in microenvironmental cells across samples, suggesting a potential contribution to the lymphoma microenvironment. Conclusions: This work demonstrates the feasibility of integrating single-cell and spatial analyses in GC lymphomas and provides a framework for investigating tumor heterogeneity and immune organization. These findings may inform future studies on biomarker development and the rational design of immunotherapies. Full article

Extracellular vesicles (EVs), as key mediators of intercellular communication, play multifaceted roles in the pathogenesis, treatment, drug resistance, and monitoring of B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). EVs derived from lymphoma cells or tumor microenvironment cells carry diverse cargoes such as proteins, microRNAs (miRNAs), and viral oncoproteins, which regulate tumor progression by modulating signaling pathways related to cell proliferation, invasion, apoptosis, autophagy, and immune suppression. In terms of treatment, accumulating evidence suggests that EVs may be associated with the efficacy of classical regimens such as R-CHOP, and they also hold potential as therapeutic targets and drug delivery vehicles for B-NHL. They contribute to drug resistance by altering the expression of key molecules or reshaping the tumor niche. Additionally, EV-derived biomarkers enable non-invasive diagnosis and monitoring of treatment response and prognosis. This review summarizes the latest research progress on the roles of EVs in major B-NHL subtypes, aiming to provide new insights for the development of innovative diagnostic and therapeutic strategies for B-NHL. Full article

Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. Full article

This study investigated highbush blueberry (Vaccinium corymbosum L.) plants cultivated in distinct cultivation systems (greenhouse vs. open field) to determine if they exhibited significant differences in rhizosphere microbiota, soil nutrient profiles, and fruit metabolites. A clear metabolic trade-off was observed: open-field cultivation significantly enhanced fruit secondary metabolites, including anthocyanins (9.5% higher), flavonoids (56.0% higher), and ascorbic acid (15.6% higher). In contrast, greenhouse fruits were enriched in primary metabolites such as water-soluble sugars (28.3% higher) and total organic acids (30.2% higher) (p < 0.01 for all comparisons). These divergent metabolite profiles were correlated with distinct rhizosphere microenvironments. The open field soil exhibited higher organic carbon and microbial α-diversity, while the greenhouse soil was characterized by a niche with high availability of cations, lower pH, higher electrical conductivity, and elevated levels of exchangeable Ca²⁺, Mg²⁺, and available potassium. These contrasting niches were correlated with shifts in the rhizosphere microbiota assembly. Notably, the greenhouse soil was associated with a higher relative abundance of copiotrophic bacterial taxa such as Streptomyces and Bacillus, whose abundances showed strong positive correlations with cation availability (e.g., Streptomyces vs. Ca²⁺, correlation coefficient r = 0.827, p < 0.01). Multivariate analysis integrated these patterns, revealing that soil cations were negatively correlated with fruit antioxidants but positively linked to sugars and acids. This correlative study suggests that cultivation systems are strongly associated with fruit quality, potentially through their association with functionally specific rhizosphere microbiota that covaries with a shift in the plant’s resource allocation between growth (primary metabolism) and defense (secondary metabolism). Our findings provide an integrative framework for understanding how agricultural practices are associated with the soil–plant–microbe continuum to correlate with crop quality in perennial systems and generate testable hypotheses for future mechanistic research. Full article

Bone is a dynamic and multifunctional tissue that provides mechanical support, regulates mineral homeostasis, supports hematopoiesis, and relies on complex interactions among multiple cell types. The increasing incidence of bone-related diseases, such as osteoporosis, osteoarthritis, fracture non-union, and bone cancer, highlights the need for in vitro models that better reflect human bone physiology. Bone-on-a-chip technology, developed through advances in microfluidics, biomaterials, and tissue engineering, offers a promising approach to recreate key features of the bone microenvironment in vitro. By incorporating bone-mimicking materials, relevant bone cells, vascular components, fluid perfusion, and mechanical stimulation, these platforms allow more realistic investigation of bone remodeling, regeneration, disease mechanisms, and drug responses. In parallel, bone organoids and their integration with microfluidic chips have further expanded the capabilities of in vitro bone models by enabling the formation of self-organized, human-relevant bone tissues with increased cellular complexity. This review summarizes recent progress in bone-on-a-chip systems, including models for osteogenesis and bone regeneration, vascularized bone, bone marrow and hematopoietic niches, cancer bone metastasis, and mechanobiological studies. Key design principles, materials, cellular components, and applications in disease modeling, drug screening, toxicity assessment, and personalized medicine are discussed. Current challenges and future directions are also discussed to support the continued development of more physiologically relevant in vitro bone models. Full article