Search Results (347)

Cervical, ovarian, and endometrial cancers comprise biologically distinct malignancies with substantial heterogeneity in their molecular alterations, metabolic dependencies, immune landscapes, and therapeutic responses. Despite advances in surgery, chemotherapy, radiotherapy, targeted therapies, and immunotherapy, these cancers remain major causes of cancer-related morbidity and mortality worldwide. Signal Transducer and Activator of Transcription 3 (STAT3) is frequently activated in these tumor types, where its biological and clinical relevance varies according to disease context, histological subtype, and molecular characteristics. In addition to tumor-intrinsic functions regulating proliferation, survival, angiogenesis, and stemness, STAT3 participates in dynamic interactions between malignant cells and the tumor microenvironment (TME), integrating inflammatory, metabolic, and stromal signals. Persistent STAT3 activation has been associated with immunosuppressive changes involving macrophage polarization, myeloid-derived suppressor cell expansion, dendritic cell dysfunction, regulatory T-cell accumulation, and impaired cytotoxic lymphocyte activity, although the extent and mechanisms of these effects differ among tumor types and experimental contexts. Metabolic alterations, including enhanced glycolysis, lactate accumulation, and hypoxia, may further interact with STAT3-dependent signaling and influence communication between tumor and stromal or immune compartments. In this review, we examine STAT3 as a signaling node linking tumor metabolism with immune regulation in cervical, ovarian, and endometrial cancers, while emphasizing disease- and subtype-specific differences. We summarize current evidence on STAT3-mediated tumor–microenvironment communication and discuss emerging STAT3-targeted therapeutic strategies. Finally, we highlight challenges related to biological heterogeneity, the lack of validated predictive biomarkers, and patient stratification that currently limit the clinical translation of STAT3-directed approaches. Full article

Immunodeficient and humanized mouse models have become essential tools for investigating human immunity, disease pathogenesis, and therapeutic evaluation. This review summarizes the stepwise evolution of these platforms, from nude and SCID mice to advanced NOD/SCID/Il2rg^null strains (NCG, NSG, or NOG), and highlights how progressive removal of murine immune barriers has improved human cell engraftment and experimental utility. Major humanized immune system (HIS) approaches, including Hu-PBMC/PBL, Hu-HSC, and Hu-BLT models, are compared with respect to engraftment kinetics, immune composition, graft-versus-host disease, and suitability for distinct research applications. Particular emphasis is placed on next-generation engineered strains that enhance specific human immune compartments, including cytokine-humanized models for myeloid, dendritic cell, natural killer cell, and neutrophil reconstitution; TSLP-based models that restore secondary lymphoid organogenesis and improve adaptive immune responses; and advanced HLA-humanized models. These advances have substantially expanded the value of humanized mice in studies of autoimmune disease, cancer immunotherapy, and vaccine evaluation. Nevertheless, no single model fully reproduces the complexity of the human immune system, and major limitations remain, including incomplete stromal humanization, restricted HLA diversity, and inter-model variability. Continued refinement will be critical for improving translational relevance and predictive power in vaccine and immunology research. Full article

Prostate cancer is the prototypical immunologically cold solid tumor, with objective response rates of only 3–5% to immune checkpoint inhibitors in unselected metastatic castration-resistant disease and an estimated 89.8% of tumors classified as immunologically ignorant. Three convergent features sustain this phenotype: low tumor mutational burden with defective Major Histocompatibility Complex class I antigen presentation; an immunosuppressive microenvironment dominated by regulatory T-cells, myeloid-derived suppressor cells, and M2 macrophages; and dense stromal and vascular barriers that exclude effector lymphocytes. Across these mechanisms, one compartment has received disproportionately little attention: the lymphatic system. Tumor-associated lymphatic remodeling driven by vascular endothelial growth factor C and D produces structurally abnormal vessels that impair antigen and dendritic cell trafficking to tumor-draining lymph nodes; the lymph nodes themselves are reprogrammed to a tolerogenic state by lymphatic endothelial cells expressing programmed death-ligand 1 and lacking costimulation and by regulatory T-cells that suppress effector egress. This review synthesizes evidence that in prostate cancer, immune coldness reflects not merely a problem of checkpoint engagement with the tumor but a failure of antigen trafficking at the lymphatic interface. We discuss therapeutic strategies that target this axis, such as lymphangiogenesis-inducing vaccines, lymph-node-directed checkpoint delivery, induction of intratumoral tertiary lymphoid structures and stromal reprogramming, as complements to existing immunotherapy. Targeting trafficking, not only checkpoints, may be the prerequisite for converting PCa from cold to hot. Full article

High-altitude pulmonary edema (HAPE) is a rapidly progressive, life-threatening disorder arising in otherwise healthy individuals upon ascent to high altitude, yet the mechanisms underlying maladaptive vascular leak remain poorly defined. Although elevated pulmonary arterial pressure and capillary stress failure are recognized as central hemodynamic drivers, accumulating evidence indicates that innate immune dysregulation is an equally critical, largely unexplored determinant of HAPE. To systematically delineate the immune and molecular programs that distinguish pathological responses to hypobaric hypoxia from acclimatization, peripheral blood along with clinical details was collected from low-altitude controls (LA-Cntrl, number of participants, (n = 19), healthy high-altitude sojourners (HA-Cntrl, n = 47), and HAPE patients (n = 90). Plasma proteomic markers were quantified using a targeted panel, while monocyte and dendritic cell subsets in peripheral blood mononuclear cells were immunophenotyped by multicolor flow cytometry. HA-Cntrl subjects displayed an anti-inflammatory profile, marked by the suppression of CXC chemokine receptor 3 axis chemokines. HAPE patients, in contrast, exhibited a pro-inflammatory, vascular injury signature, with elevated levels of inflammatory interleukins and myeloid and chemotactic factors. This inflammatory signature was accompanied by the expansion of classical monocytes, implicating a myeloid vascular program associated with HAPE. Full article

Hepatic inflammation is a defining feature of Metabolic Dysfunction-Associated Steatohepatitis (MASH), yet the specific contributions of individual immune cell populations and their reciprocal interactions remain incompletely understood. In this study, we combined flow cytometry with single-cell transcriptomic profiling to characterize the hepatic immune landscape in a novel model of spontaneous MASH caused by hepatocyte-specific deficiency of endoplasmic reticulum-associated degradation (ERAD). Hepatic ERAD deficiency led to the expansion of multiple immune cell populations in the liver, including CD8+ T cells, macrophages, monocytes, and dendritic cells, accompanied by extensive functional reprogramming of both innate and adaptive immune compartments. Myeloid cells exhibited enhanced phagocytic activity and increased antigen processing and presentation, whereas CD8+ T cells displayed elevated proliferation capacity, DNA repair activity and cytotoxicity. Notably, two functionally distinct triggering receptor expressed on myeloid cells 2 (TREM2)-expressing macrophage subsets emerged during the progression of ERAD deficiency-induced MASH. Depletion of CD8+ T cells increased monocyte infiltration and aggravated liver injury, suggesting that CD8+ T cells exert a previously unrecognized protective role by restraining monocyte recruitment. Collectively, these findings reveal highly coordinated interactions between innate and adaptive cells during MASH progression and identify CD8+ T cells as potential regulators of monocyte infiltration and hepatic injury. Full article

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically “cold” tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites. Full article

Persistent HIV-1 reservoirs remain a major barrier to a durable functional cure despite long-term suppressive antiretroviral therapy. Although resting memory CD4⁺ T cells constitute the best-characterized cellular reservoir, tissue microenvironments shape viral persistence and immune clearance. The rectal mucosa represents a specialized tissue niche containing HIV-susceptible target cells, antigen-presenting cells, microbial products, inflammatory cues, and local metabolic signals. Within this setting, myeloid-lineage cells, particularly tissue-resident macrophages and dendritic cells, may contribute to HIV-1 persistence through mechanisms distinct from classical T-cell latency. Here, we review how rectal mucosal macrophages may support HIV-1 persistence through longevity, resistance to apoptosis, metabolic adaptation, epigenetic regulation, and sequestration of virions within virus-containing compartments. We also discuss the dual role of mucosal dendritic cells as sentinels that capture and transfer HIV-1 to CD4⁺ T cells, while considering the limited evidence for inducible proviral persistence in selected anatomical and cellular contexts. Importantly, we further distinguish bona fide reservoir-bearing cells from reservoir-supportive mechanisms, including viral capture, trans-infection, immune suppression, and niche-mediated protection. We also highlight how mucosal dysbiosis, barrier disruption, microbial metabolites, chronic interferon signaling, and immunoregulatory myeloid programs may stabilize HIV-1 persistence in rectal tissues. Integrating intact proviral assays, functional measurements, single-cell profiling, multiplex imaging, and spatial transcriptomics will be critical for defining myeloid-associated persistence and guiding tissue-targeted HIV-1 cure strategies. Full article

Background: Fasting-mimicking diets (FMDs) induce metabolic changes associated with immunomodulation in preclinical studies, yet little is known about the effects of FMD on the human circulating immune system. Methods: In the single-arm FIND pilot study (NCT04833439), six of nine healthy participants completed two cycles of a 4-day FMD separated by 3 weeks of regular diet in a repeated-measures design. Blood samples were collected at baseline, after an overnight fast, and the morning after completion of the second FMD cycle. Peripheral blood mononuclear cells (PBMCs) were analyzed by transcriptomic profiling and spectral flow cytometry. Results: FMD was associated with reduced plasma glucose and insulin-like growth factor-1 and increased ketone levels. Transcriptomic analysis showed increased expression of genes involved in the TNFα, IFNγ and IFNα signaling pathway after two FMD cycles. Fifteen of the 39 leading-edge genes of the TNFα signature that have previously been associated with myeloid activity and rapid stress responses corresponded with the increased frequencies of circulating CD14-CD11b-CD11c+ dendritic cells (DCs), CD123+ plasmacytoid DCs, and CD14+ CD16+ intermediate monocytes. Moreover, the frequencies of HLA-DR-expressing CD4+ and CD8+ T-cells increased (p < 0.05) after two FMD cycles. Conclusions: In healthy volunteers, two cycles of FMD were associated with metabolic changes and alterations in circulating myeloid and T-cell populations consistent with activation of selected inflammatory pathways. These exploratory findings warrant larger validation studies in healthy volunteers in combination with functional analyses. Full article

Background/Objectives: Brain arteriovenous malformations (bAVMs) are complex cerebrovascular lesions that carry a substantial risk of intracranial hemorrhage, yet the biological mechanisms underlying vascular remodeling remain incompletely understood. As increasing evidence suggests that inflammatory processes contribute to vascular remodeling and bAVM progression, this study aimed to characterize the cellular composition of the immune microenvironment in human bAVMs at single-cell resolution and to identify immune cell populations associated with transcriptional programs related to angiogenesis and extracellular matrix remodeling. Methods: Publicly accessible single-cell RNA sequencing data from five human bAVM samples and five control brain specimens were analyzed. After quality control and data integration, immune cell types were annotated based on canonical marker gene expression. To assess biological processes relevant to vascular remodeling, the expression of predefined gene sets associated with angiogenesis and extracellular matrix remodeling, derived from the Molecular Signatures Database (MSigDB), was quantified across cell populations using rank-based gene set scoring (UCell). Differences between bAVM and control samples were evaluated at the sample level using the Wilcoxon rank-sum test. For each immune cell type, mean UCell scores were calculated per biological sample and compared between groups. To account for multiple comparisons across cell types, p-values were adjusted using the Benjamini–Hochberg procedure. Results: After quality control, 46,360 immune cells were analyzed. Compared with control tissue, bAVMs showed numerically higher proportions of lymphoid (activated T cells and CD8 T cells) and myeloid populations (M1-like macrophages, monocytes, and dendritic cells). Angiogenesis-related transcriptional activity was highest in myeloid cells and significantly increased in bAVMs, particularly in M1-like macrophages (UCell score 0.22 vs. 0.13), dendritic cells (0.16 vs. 0.10) and monocytes (0.20 vs. 0.15), whereas proliferating CD8 T cells showed a lower score (0.04 vs. 0.05; adjusted p = 0.040 for all four). Extracellular matrix-related programs showed a similar but weaker and non-significant pattern in myeloid populations (e.g., monocytes, dendritic cells, microglia-like cells; adjusted p = 0.09). Conclusions: Our findings identify myeloid cells, particularly M1-like macrophages, monocytes and dendritic cells, as important immune populations associated with angiogenesis in bAVMs. These findings highlight a potential role of immune-driven vascular remodeling in the pathophysiology of bAVMs. Full article

Therapeutic cancer vaccines are designed to initiate tumor-specific immunity, yet their clinical success depends not only on antigen selection but also on the capacity to overcome the profoundly suppressive tumor microenvironment. Within tumors, abnormal vasculature, hypoxia, nutrient competition, acidic pH, and suppressive myeloid and stromal cells collectively constrain antigen presentation, T-cell priming, trafficking, and effector function, often converting otherwise immunogenic vaccination into an ineffective immune stimulus. Recent advances in neoantigen discovery, dendritic cell engineering, and nucleic acid-based vaccine platforms have improved the precision of antigen delivery, but these gains remain insufficient unless vaccine-induced responses can be sustained and executed within the hostile metabolic and immunologic landscape of the tumor niche. In this context, the tumor microenvironment is not merely a barrier to be overcome, but an active determinant of vaccine outcome that shapes immune editing, promotes exhaustion, and limits intratumoral expansion of cytotoxic lymphocytes. Accordingly, the most promising therapeutic strategies now combine vaccination with checkpoint blockade, radiotherapy, stromal remodeling, or metabolic reprogramming to recondition the tumor ecosystem and permit productive antitumor immunity. Here, we discuss how tumor microenvironmental constraints govern vaccine performance, review emerging platform technologies, and outline combinatorial strategies aimed at converting immune priming into durable tumor control. Full article

Urothelial carcinoma (UC) is a biologically and clinically heterogeneous disease arising from the bladder and upper urinary tract. Immune checkpoint inhibitors (ICIs) have transformed treatment of advanced UC, yet durable responses remain limited to a minority of patients, underscoring the need to better understand the tumor immune microenvironment (TME). This narrative review examines the UC immune phenotype across disease stages and anatomical sites, integrating evidence from bulk and single-cell transcriptomics, spatial profiling, and translational studies. We describe the principal immune cell populations of the UC TME—including cytotoxic and regulatory T cells, macrophages, myeloid-derived suppressor cells, natural killer cells, B cells, and dendritic cells—and their relationship to established molecular subtypes. We review how this immune landscape evolves from non-muscle-invasive to metastatic disease, including the distinct contexture of upper tract UC and variant histology. We critically evaluate established ICI biomarkers (PD-L1, FGFR3, tumor mutational burden, mismatch repair deficiency) alongside emerging candidates—tumor-infiltrating lymphocyte density, HLA class I expression, tertiary lymphoid structures, and multiparameter transcriptomic scores—noting that most remain investigational and require prospective validation before clinical use. Finally, we address key biological, technical, and clinical barriers to this research and outline future directions in AI-assisted digital pathology and multimodal biomarker integration. A comprehensive characterization of UC immune phenotype is essential to guide rational, biomarker-driven patient selection and optimize next-generation immunotherapy strategies. Full article

Alpha-enolase (ENO1) is a multifunctional protein frequently overexpressed in solid tumors, where elevated levels are associated with aggressive behavior and poor prognosis. Beyond its canonical glycolytic role, ENO1 participates in immunoregulatory processes through distinct subcellular pools. Intracellular ENO1 shapes tumor-associated metabolic programs, while surface-exposed ENO1 functions as a plasminogen receptor and can engage innate immune signaling pathways. Post-translational modifications—particularly citrullination and phosphorylation—generate structurally altered epitopes that expand ENO1 antigenicity and enable adaptive immune recognition, including coordinated humoral and T-cell responses in cancer patients. These determinants of ENO1 immunogenicity have downstream consequences within the tumor microenvironment: immune-accessible ENO1 modulates myeloid cell recruitment, dendritic cell maturation, and macrophage polarization, while ENO1-dependent metabolic and signaling programs contribute to immune suppression and escape through multiple interconnected axes. Together, these mechanisms position ENO1 at the interface between tumor metabolism and immune regulation. Preclinical evidence demonstrates that ENO1-directed strategies—including antibody-based targeting, DNA vaccination, and vaccines incorporating post-translationally modified ENO1 peptides—can generate productive antitumor immunity and synergize with checkpoint blockade, supporting the rationale for ENO1 as an immunotherapeutic target. This review synthesizes current evidence within an integrated framework linking ENO1 dysregulation to its immunological consequences in cancer and discusses translational implications for ENO1-centered immunotherapy and immunoprevention. Full article

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy characterized by high mortality and a rising incidence. Although immune checkpoint inhibitors have significantly improved patient outcomes, many patients exhibit primary or acquired resistance, frequently in the setting of an immunosuppressive tumor microenvironment (TME) enriched for myeloid populations. This review synthesizes current evidence and proposes a testable model in which nicotinic acetylcholine receptor (nAChR) signaling may intersect with tumor-associated macrophage (TAM) biology to reinforce immune exclusion in MCC. Direct MCC-specific evidence currently supports nAChR-subunit expression in tumor tissues and the association of CD163⁺/CD14⁺/S100A8⁺ myeloid populations with resistance to PD-1 pathway blockade; however, functional nAChR signaling in MCC tumor cells, TAMs, or dendritic cells has not yet been demonstrated. We therefore distinguish established MCC observations from mechanistic hypotheses extrapolated from macrophage biology, cholinergic anti-inflammatory signaling, and other cancer models. Within this framework, α7-nAChR signaling on TAMs may activate the cholinergic anti-inflammatory pathway and favor suppressive myeloid states, whereas α3- and α5-containing receptors detected in MCC tumor cells may represent tumor-cell-associated candidates for future mechanistic testing. By integrating evidence on TAM plasticity, spatial immune exclusion, and cholinergic signaling, we propose that the nAChR–macrophage axis is a rational but unproven therapeutic hypothesis that warrants systematic validation in MCC models. Full article

Glutathione peroxidase 4 (GPX4) is canonically viewed as the primary suppressor of ferroptosis, yet its role in the tumor microenvironment (TME) extends far beyond antioxidant catalysis to encompass immuno-metabolic regulation. In this review, we synthesize recent advances in enzymology, immunology, and cancer metabolism to propose a “lipid peroxidation threshold” framework, wherein GPX4 sets cell-type-specific thresholds that determine susceptibility to ferroptosis across tumor cells, CD8⁺ T cells, dendritic cells (DCs), and myeloid populations. We discuss how these thresholds are dynamically adjusted by post-translational modifications, nutrient competition and intercellular feedback loops, resulting in significant spatial heterogeneity between the tumor core and the tumor invasive front. There is a current selectivity paradox in GPX4 inhibitors, as well as resistance through nuclear factor erythroid 2-related factor 2 (Nrf2) and ferroptosis suppressor protein 1 (FSP1) that restricts the efficacy of GPX4 inhibitors as monotherapy. We focus on rational combination approaches: GPX4 modulation with immune checkpoint blockade (ICB), chemotherapy, and targeting myeloid-derived suppressor cells (MDSCs); and the pressing need for predictive biomarkers and single-cell spatial profiling. We conclude that successful clinical translation requires moving beyond indiscriminate GPX4 inhibition toward precision “threshold engineering” that selectively lowers tumor lipid peroxidation thresholds while sparing immune cells. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in cancer and represent one of the major drivers of tumor-associated immunosuppression. MDSCs actively contribute to tumor progression by inhibiting both innate and adaptive immune responses, promoting angiogenesis, metastatic dissemination, and resistance to immunotherapy. Two major subsets have been identified, polymorphonuclear (PMN-) and monocytic (Mo-) MDSCs, each characterized by distinct phenotypic, metabolic, and suppressive properties. Within the tumor microenvironment (TME), MDSCs establish a complex network of interactions with T-, B-, NK-cells, dendritic cells, and macrophages, thereby orchestrating immune escape and tumor persistence. Recent evidence highlights the pivotal role of metabolic rewiring in regulating MDSC survival and suppressive activity. Enhanced aerobic glycolysis, fatty acid oxidation, amino acid depletion, reactive oxygen species (ROS) production, and adenosine metabolism collectively sustain MDSC-mediated immune dysfunction and shape the immunosuppressive TME. In particular, the crosstalk between PMN-MDSCs and NK cells has emerged as a critical mechanism of tumor immune evasion, leading to impaired NK cell cytotoxicity, altered activating receptor expression, and defective cytokine production. In this review, we summarize the current knowledge on the phenotypic and functional heterogeneity of MDSCs, their metabolic adaptations, and their interactions with immune effector populations in cancer. Furthermore, we discuss emerging therapeutic strategies aimed at targeting MDSC recruitment, differentiation, metabolic pathways, and suppressive functions. Understanding the molecular and metabolic mechanisms governing MDSC biology may provide novel opportunities to overcome tumor-induced immunosuppression and improve the efficacy of current cancer immunotherapies. Full article