Search Results (751)

Background: Lung adenocarcinoma (LUAD) develops through a stepwise pathological status from atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA) to invasive adenocarcinoma (IA). Although malignant epithelial evolution during this process has been increasingly characterized, the dynamic remodeling of cancer-associated fibroblasts (CAFs) and their contribution to the immunosuppressive tumor microenvironment (TME) remain incompletely explored. Methods: Single-cell RNA sequencing data from treatment-naïve LUAD lesions, including AAH, AIS, MIA, and IA, were analyzed together with external bulk transcriptomic cohorts. CAF subsets were characterized according to their transcriptional features, inferred developmental states, transcription factor activity, functional programs, and predicted cell–cell interactions. Ligand–receptor analysis was used to examine MIF-related communication between epithelial cells and CAFs. MIF-related genes were then used to develop a machine learning-based prognostic signature in the TCGA-LUAD cohort, followed by validation in independent GEO cohorts. Results: Single-cell transcriptomic analysis of 131,639 cells from 25 treatment-naïve LUAD lesions identified six CAF subtypes, including alveolar CAFs, antigen-presenting CAFs, extracellular matrix CAFs, EndMT-like CAFs, inflammatory CAFs, and myofibroblastic CAFs. CAF composition differed across pathological stages, with MIA lesions showing a distinct enrichment of eCAFs and reduced proportions of inflammatory and myofibroblastic CAF populations. Compared with pre-invasive lesions, IA lesions exhibited increased proportions of exhausted CD4+ and CD8+ T cells together with reduced cytotoxic features. Cell–cell communication analysis identified enhanced epithelial–CAF interactions in IA, including enrichment of MIF-CD74/CD44 signaling. Based on MIF-related genes, a machine learning prognostic signature was developed and validated in independent cohorts, consistently stratifying patients into distinct risk groups with significantly different survival outcomes. Conclusions: These findings suggest that CAF-related stromal remodeling is associated with immune suppression during LUAD progression. MIF-mediated epithelial–CAF communication may be involved in the formation of an immunosuppressive microenvironment and is associated with poor prognosis. The MIF-related signature may provide a useful approach for prognostic stratification in LUAD. Full article

Multiple myeloma (MM) is a genetically and clinically heterogeneous plasma cell malignancy characterised by clonal expansion of differentiated B cells within the bone marrow (BM). Patients start with monoclonal gammopathy of undetermined significance (MGUS) and progress to an intermediate stage called smouldering multiple myeloma (SMM), characterised by several genetic alterations that represent the genomic backbone of the malignant clone. Immune checkpoint pathways play a central role in shaping an immunosuppressive BM niche, contributing to T-cell dysfunction, immune evasion, and therapeutic resistance. Key inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and CD47 are frequently dysregulated, promoting T-cell exhaustion, anergy, and senescence. Emerging evidence highlights extracellular vesicles (EVs) as critical mediators of intercellular communication in MM. MM-derived EVs carry bioactive cargo, including proteins and miRNAs, that reprogram immune and stromal cells, enhancing tumour progression and immune escape. Notably, EV-associated immune checkpoint molecules contribute to the establishment of a permissive microenvironment. This review provides an integrated overview of immune checkpoint dysregulation and EV-mediated immunomodulation in MM, emphasising their role in disease pathogenesis and progression. Furthermore, we discuss the therapeutic potential of targeting immune checkpoints and exploiting EVs as novel biomarkers and drug delivery systems, highlighting their promise for improving precision medicine approaches in MM. Full article

Immunotherapies, including chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers (BiTEs), and antibody–drug conjugates (ADCs), have revolutionized the treatment landscape for multiple myeloma (MM). Despite robust initial response rates, achieving durable remissions remains challenging due to frequent relapses driven by complex therapeutic resistance mechanisms. In this review, we comprehensively examine intrinsic tumor resistance, such as innate and acquired antigen escape mediated by genomic alterations, structural variations, and epigenetic silencing. Furthermore, we highlight the critical role of the highly permissive bone marrow microenvironment in blunting the efficacy of modern therapies. Cellular compartments, including mesenchymal stromal cells, osteoclasts, and expanded immunosuppressive immune populations, actively foster tumor survival, promote metabolic competition, and T-cell exhaustion. We also review the unique clinical toxicities associated with T-cell-redirecting modalities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Ultimately, deciphering the complex interplay between malignant plasma cells and their surrounding microenvironment is essential for optimizing treatment sequencing, preventing effector cell exhaustion, and designing next-generation therapeutic strategies to secure long-term, durable responses for patients. Full article

Tumour development and progression involve complex cell-cell interactions and dynamic co-evolution between cancer cells, immune cells and stromal cells in the tumour microenvironment and this may influence therapeutic resistance. A large proportion of this network relies on direct physical interactions between cells, particularly T-cell mediated interactions. Cell-cell communication inference has now become routine in downstream scRNAseq analysis but this mostly fails to capture physical cell-cell interactions due to tissue dissociation. Doublets occur naturally in scRNA-seq and are usually excluded from analysis. However, they may represent directly interacting cells that remain undissociated during library preparation. In the present study, we uncover the physical interaction landscape of the ovarian tumour microenvironment using the scRNAseq datasets from 13 treatment-naive ovarian cancer patients. Focusing on T-cell-Macrophage (T-Mac) interaction doublet, we reveal the modulatory effect of macrophages on T cells and the potential influence of this interaction on therapeutic response. Our findings show that T-Macs from resistant patients are functionally polarized to the M2 phenotype and engage T cells to induce T-cell exhaustion. Whereas, T-Macs from sensitive patients are predominantly of the M1 polarized phenotype, physically engaging T cells that lack exhaustion signatures. We also demonstrate that T cells and macrophages in T-Mac doublet are interacting primarily for the purpose of antigen presentation, with the enrichment of several ligand-receptor pairs involved in TCR-MHC interactions and immune synapse formations. We partly validated some of these findings from a spatial transcriptomics dataset of ovarian cancer patients from a separate cohort. Full article

Chemotherapy resistance in triple-negative breast cancer (TNBC) remains a critical clinical challenge, with a substantial proportion of patients failing to achieve pathological complete response following neoadjuvant chemotherapy (NAC). Using an integrative single-cell RNA sequencing (scRNA-seq), bulk transcriptomic, and spatial proteomic framework, we aimed to identify the malignant epithelial subset driving this resistance and the intercellular signaling axes through which it reprograms the tumor microenvironment (TME). scRNA-seq analysis of NAC-treated breast tumors revealed a Fatty Acid–EMT co-expressing epithelial subset (FA-EMT) that is selectively enriched in the chemotherapy-resistant residuum. Critically, FA-EMT co-expression—rather than either program individually—most powerfully predicted chemotherapy resistance and reduced overall survival across two independent bulk transcriptomic cohorts comprising 277 TNBC patients (p < 0.001). CellChat ligand–receptor analysis established FA-EMT cells as the dominant TME signaling hub, deploying MDK–NCL and MIF–CD74–CXCR4 axes to simultaneously suppress adaptive and innate anti-tumor immunity via T-cell exhaustion, Treg activation, and the expansion of myeloid-derived suppressor cells. Spatial CyCIF validation in a published paclitaxel-resistant TNBC mouse model (n = 69 cores) confirmed significant Metabolic-EMT enrichment in resistant tumor cores (p = 0.0085) with physical co-localization with immunosuppressive MDSC and Treg populations. These findings establish the FA-EMT subset as a key cellular driver of treatment failure in TNBC and nominate MDK–NCL and MIF–CD74–CXCR4 as mechanistically grounded therapeutic targets with the potential to dismantle the FA-EMT-driven immunosuppressive niche and sensitize chemotherapy-resistant TNBC to cytotoxic treatment. Full article

Ebola virus disease (EVD) has traditionally been considered an acute infection characterized by high mortality and severe systemic inflammation. However, growing evidence accumulated over the last decade has progressively challenged this view, demonstrating that Ebola virus may persist long after apparent clinical recovery within immune-privileged anatomical compartments, including the male genital tract, ocular tissues, central nervous system, and breast milk. Persistent viral reservoirs have been associated with prolonged RNA shedding, sexual transmission, recrudescence phenomena, and outbreak resurgence, highlighting the clinical and public health relevance of post-acute Ebola persistence. At the same time, increasing evidence suggests that EVD survivors frequently exhibit chronic inflammatory activation and long-lasting immune dysfunction. Persistent alterations involving cytokine signaling, T-cell responses, and antiviral immune regulation may contribute to incomplete viral clearance and reservoir maintenance. In this context, the potential interaction between Ebola virus persistence and HIV-associated immune dysregulation remains poorly explored despite the substantial geographical overlap between both infections in sub-Saharan Africa. This narrative review examines current evidence regarding Ebola virus persistence, immune-privileged reservoirs, survivor immune dysfunction, and persistence-associated transmission. Additionally, we discuss the biological plausibility that chronic immune activation, T-cell exhaustion, and impaired antiviral surveillance observed in people living with HIV (PWH) could theoretically influence persistence dynamics and long-term reservoir biology. Understanding these interactions may have implications for survivor monitoring, outbreak preparedness, and future research on post-acute viral reservoir diseases. Importantly, this review does not argue that HIV has been clinically established as a modifier of Ebola virus persistence. Rather, it examines Ebola virus persistence as an established post-acute phenomenon and considers whether HIV-associated immune dysregulation in people living with HIV (PWH) may represent a biologically plausible, but still untested, determinant of viral clearance and reservoir biology. Full article

Chronic lymphocytic leukemia (CLL) is characterised by the dependence of malignant cells on specialised tissue microenvironments within the bone marrow (BM) and secondary lymphoid organs (SLOs), which provide essential survival and proliferative signals. The CXCR4/CXCL12 and CXCR5/CXCL13 chemokine axes direct the trafficking of CLL cells into these anatomically distinct compartments, where stromal-derived survival signals protect them from both spontaneous and therapy-induced apoptosis. Although each chemokine axis has been extensively studied individually, no previous review has integrated both pathways into a unified mechanistic framework. This review proposes that the signal transducer and activator of transcription 3 (STAT3) function as a shared molecular hub that integrates niche-derived cytokine signals, including interleukin-6 (IL-6), IL-10, and IL-21, and may transcriptionally upregulate both CXCR4 and CXCR5, and reinforce tissue homing through a positive feedback loop. This review seeks to evaluate the expression, signalling, and clinical significance of each axis, their points of convergence and divergence and the therapeutic strategies that disrupt these parallel homing pathways. Complementing this framework, recent clinical evidence indicates that circulating CXCL13 serves as a robust prognostic biomarker in CLL, and that STAT3 inhibition may overcome bone marrow stromal-mediated cytoprotection. The CXCL12-CXCR4-STAT3-IL-10 immunosuppressive axis further drives T-cell exhaustion. Together, these pathways form an integrated oncogenic network that supports CLL cell survival, drives immune dysfunction, and promotes therapy resistance. Several important knowledge gaps remain. These include the lack of direct validation of the STAT3-CXCR5 transcriptional axis in primary CLL cells and uncertainty regarding whether CXCR4/CXCR5 dominance represents a stable transcriptional programme or a dynamic, microenvironment-driven process. Addressing these questions through single-cell transcriptomics, spatial transcriptomics, proteomics, and functional validation studies will be essential for developing rational combination therapies capable of simultaneously disrupting both homing axes. Full article

High-grade serous ovarian carcinoma (HGSOC) shows limited benefit from immune checkpoint blockade, partly because stromal barriers impair antitumor immunity. We developed a cancer-associated fibroblast (CAF)-associated mitochondrial metabolic and matrix-remodeling signature, termed CMMS, to characterize this immune-suppressive stromal state. CMMS integrated contractile/myCAF, extracellular matrix (ECM), and mitochondrial metabolic genes. Its clinical, metabolic, and immune relevance was evaluated in TCGA-HGSOC, independent GEO cohorts, single-cell RNA-seq datasets, and an anti-PD-L1-treated cohort, followed by cell–cell communication and experimental validation. LASSO-weighted CMMS stratified overall survival, with high CMMS indicating poorer prognosis. CMMS-high tumors exhibited ECM/TGFβ activation; associations with COL1A1, POSTN, and LOX; and a hypoxia-dominant metabolic phenotype. Mediation analysis suggested that hypoxia largely linked CMMS to glycolytic remodeling. Immune profiling revealed stromal-rich immune exclusion, checkpoint activation, and exhaustion-prone T-cell dysfunction. Single-cell analysis localized CMMS mainly to myCAF-like ECM-remodeling CAFs. In validation datasets, CMMS-high CAFs were associated with reduced CD8 abundance, increased CD8 exhaustion, and stronger matrix- and chemokine-related communication with T cells. Experiments further supported a link between TGFβ-related fibroblast activation, ECM-remodeling features, and impaired CD8⁺ T-cell effector function. Overall, CMMS defines a CAF-enriched fibrotic–hypoxic stromal program associated with immune exclusion-related features, exhaustion-prone T-cell dysfunction, and poor outcome in HGSOC. Full article

Largemouth bass (Micropterus salmoides) is a major aquaculture species in China. Facility-based aquaculture, such as the “168” model, a high-efficiency recirculating system using funnel-shaped ponds, has promoted water conservation and improved aquaculture efficiency through structural innovation. However, fish die sporadically as the stocking density increases with increasing fish growth. To address this issue, three density groups were established, namely, low (2.5 ± 0.5 kg/m³), medium (4.0 ± 0.5 kg/m³), and high (7.5 ± 0.5 kg/m³). Histological examinations, biochemical assays, and transcriptomic and metabolomic analyses of liver tissues were performed, and fish health was comprehensively evaluated. Histopathological analysis revealed that progressive hepatic vacuolization and severe tissue damage occurred as the fish density increased. Biochemical indicators revealed that the immune system and growth underwent compensatory activation at medium density, shifting to immune suppression, growth impairment, and hepatic exhaustion at high density. Integrated omics analysis revealed that under medium-density stress, the urea cycle was impaired; under high-density stress, Ser metabolism in the liver was rerouted, potentially to overcome methyl donor depletion and prevent disorders of polyamine metabolism, accompanied by a gradual transition from compensatory activation to functional exhaustion. These findings improve our understanding of the physiological response mechanisms of fish to high-density stress. This study provides a theoretical basis for optimizing high-density aquaculture technologies such as the “168” model. Full article

Aging is accompanied by complex structural and functional immune system changes driven by genomic instability, epigenetic alterations, mitochondrial dysfunction, telomere attrition, loss of proteostasis, deregulated nutrient sensing, and the accumulation of senescent cells exhibiting a senescence-associated secretory phenotype, which altogether lead to severe consequences including altered antimicrobial defense, the overproduction of autoantibodies, and chronic, low-grade inflammation (inflammaging). In this article, we summarize age-related alterations in the function of primary and secondary lymphoid organs, including the bone marrow, thymus, spleen, and lymph nodes. The involution of these organs leads to impaired hematopoiesis, reduced production of naïve lymphocytes, and immune microenvironment disruption. We also describe aging-related impairment of the activity of neutrophils, macrophages, dendritic cells and natural killer cells, as well as dysregulation of T and B lymphocyte responses. Specifically, these alterations include a decline in naïve cell populations, an accumulation of memory and exhausted cells, and a reduction in the diversity of antigen receptors. Consequently, older individuals exhibit increased susceptibility to infections, cancer, and autoimmune diseases, along with diminished vaccine efficacy. Understanding the mechanisms underlying immune aging could lay the foundation for developing therapeutic strategies and lifestyle interventions to mitigate the adverse effects of this unfavorable process. Full article

Cartilage oligomeric matrix protein (COMP) influences extracellular matrix remodeling. We investigated its clinical, prognostic, and immunomodulatory significance in colorectal cancer (CRC). COMP was quantified via ELISA in 107 paired CRC and normal tissues. Expression was correlated with clinicopathological features, mutational profiles, microsatellite instability (MSI), tumor-infiltrating lymphocytes (TILs), immune checkpoints, and multiplex cytokine networks. For transcriptomic validation, the FieldEffectCrc dataset was used for Gene Set Enrichment Analysis (GSEA), and The Cancer Genome Atlas (TCGA) CRC cohort for survival analysis. COMP was significantly upregulated in CRC tissues (p < 0.001) and correlated with advanced T, N, and overall pathological stages (all p < 0.05, tau = 0.18, 0.21, and 0.23, respectively). High COMP expression was linked to restricted immune infiltration (reduced stromal TILs, p < 0.05, tau = −0.23), elevated levels in microsatellite stable (MSS) compared to MSI tumors (p < 0.01), and correlated positively with immune exhaustion markers (T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), galectin-9 (GAL9), sialic acid-binding Ig-like lectin 9 (SIGLEC9)). Transcriptomic data linked high COMP to worse disease-specific and progression-free survival, and enrichment in pro-tumorigenic pathways (epithelial-to-mesenchymal transition, angiogenesis, IL-6 signaling). COMP upregulation defines an immunosuppressive microenvironment in CRC, particularly in MSS tumors. It represents an important prognostic biomarker and potential therapeutic target for overcoming immunotherapy resistance. Full article

Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel–Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical “immune-hot yet immunosuppressed” phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy. Full article

Insect antimicrobial peptides (AMPs) are classically viewed as terminal effectors of innate immunity, but emerging evidence suggests that some can also shape defined neural states. In this Review, we argue that insect systems provide a powerful framework for resolving immune–brain communication at the level of individual peptide effectors, because genetically tractable innate-immune pathways allow pathway activation to be distinguished from peptide-specific effector function. Rather than surveying AMP families exhaustively, we focus on representative cases in which peptide identity, source, and timing can be linked to sleep, memory-related plasticity, and responses to acute injury. These studies show that the neural consequences of AMP induction cannot be inferred from pathway activation alone, but require peptide-level analysis of effector identity, cellular context, and exposure logic. This perspective also raises the question of translational potential. At present, direct biomedical development of endogenous insect AMPs in neural contexts remains limited, whereas more tangible applied interest has centered on insect venom peptides that share AMP-like physicochemical features. We therefore discuss insect venoms separately from endogenous AMP physiology. Venom peptides are not physiological equivalents of endogenous insect AMPs, but represent evolutionarily diversified AMP-like templates for scaffold discovery, mechanistic probing, and therapeutic engineering. Together, this review develops a peptide-level perspective on insect neuroimmune biology while highlighting insect venoms as a valuable, but highly constrained, source of templates for biomedical discovery. Full article

CD8⁺ T-cell exhaustion is a key mechanism of tumor immune evasion and a major limitation of current cancer immunotherapy. However, the molecular factors sustaining dysfunctional CD8⁺ T-cell states across cancers are not fully understood. Here, we identify GPR171 as a common feature of exhausted CD8⁺ T cells across multiple solid tumors based on integrated pan-cancer single-cell transcriptomic analyses. GPR171 is enriched in exhausted CD8⁺ T cells and is closely associated with immunosuppressive and exhaustion-related gene programs. It also shows a strong association with key immune regulatory genes such as CTLA4 and NR4A2. Functional analyses suggest that reduced GPR171 activity is associated with decreased expression of exhaustion-related genes and a shift toward cytotoxic and immune-activating programs. In parallel, a CREM-centered regulatory network emerges in exhausted CD8⁺ T cells and may act in concert with GPR171-associated programs to reinforce dysfunctional states. Overall, our results identify GPR171 as a candidate marker of CD8⁺ T-cell dysfunction across cancers and provide a systematic pan-cancer single-cell characterization of its association with immunosuppressive T-cell states, supporting its potential as a therapeutic target for restoring antitumor immunity. Full article

Patients with cancer are at increased risk of severe outcomes from COVID-19. Yet, the immunological determinants underlying this vulnerability remain incompletely understood, particularly in low- and middle-income settings. Moreover, the impact of the severe viral disease surge and its compensatory mechanisms, such as stressed myelopoiesis, on this population needs further elucidation. This study aims to characterize the cytokine and lymphocyte profiles of cancer patients with COVID-19, correlate these profiles with disease severity, and compare them to those of non-cancer patients with COVID-19. Plasma cytokine, chemokine, and growth factor levels were quantified using Luminex technology, and immune cell subsets were characterized by flow cytometry. A total of 67 patients were analyzed: 40 with cancer (26 mild cases and 14 severe cases) and 27 without cancer (12 mild cases and 15 severe cases). Clinical outcomes showed an 86% mortality rate in cancer patients due to severe COVID-19. This contrasted with a 3.8% mortality rate in cancer patients with mild COVID-19, all unrelated to the infection. Our findings revealed elevated CXCL10 (IP-10) and reduced MIF levels in cancer patients with COVID-19, distinguished by disease severity. Compared with that in cancer patients with mild COVID-19, the level of CXCL10 in cancer patients with severe COVID-19 was further elevated. Additionally, cancer patients with COVID-19 presented reduced CD3⁺ T lymphocytes, expansion of CD4⁺CD25⁺FoxP3⁺ regulatory cells and CD56^BRIGHT NK cells, a shift from effector memory to central memory T-cells, and increased numbers of exhausted (PD-1⁺) T lymphocytes. In conclusion, our data suggest a distinct immunological profile observed in cancer patients with COVID-19. Especially in severe cases, viral surge-related suppressor cells and proinflammatory cytokines were accompanied by a compensatory immunosuppressive state, with decreased effector function and increased exhaustion. This may negatively impact clinical outcomes and highlight potential implications for the management of cancer patients. Full article