Frontiers in Immunology最新文献

{"title":"An opsonic peptide promotes radiation-induced macrophage extracellular trap clearance to alleviate inflammation.","authors":"Yongchan Lee, Gaifeng Ma, Dilara Aylar, Monowar Aziz, Ping Wang","doi":"10.3389/fimmu.2026.1970645","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1970645","url":null,"abstract":"<p><p>Ionizing radiation exposure leads to inflammation and tissue damage, in which macrophage extracellular traps (METs) may play a role. Effective strategies to mitigate inflammation caused by radiation-induced METs are needed. We have recently developed a novel opsonic peptide, OP18, that targets multiple damage-associated molecular patterns (DAMPs) and enhances their clearance by macrophages. Because METs contain DAMPs, including histone H3 and high-mobility group box 1 protein (HMGB1), we hypothesize that OP18 promotes the clearance of radiation-induced METs and thereby reduces inflammation. <i>In vitro</i> studies were conducted using macrophages exposed to radiation and METs, with or without OP18 treatment. METs uptake, endo-lysosomal trafficking, integrin involvement, mitochondrial function, NF-κB activation, and cytokine release were assessed. OP18 significantly enhances MET uptake by macrophages, an effect that is mediated by α_vβ₃-integrin and involves the endo-lysosomal trafficking. This enhanced clearance by OP18 alleviates METs-induced mitochondrial stress and restores metabolic function (ATP production, basal/maximal respiration) in macrophages. Furthermore, OP18 treatment exhibits a trend towards decreasing METs-induced NF-κB activation while increasing the release of anti-inflammatory cytokine IL-10. OP18 represents a novel therapeutic approach to mitigate radiation-induced inflammation by promoting the efficient clearance of pro-inflammatory METs, thereby restoring cellular homeostasis and dampening inflammatory signaling.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1970645"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Genetically defined systemic autoinflammatory diseases in pediatric patients with Behçet's disease.","authors":"Shaoling Zheng, Pui Y Lee, Qing Zhou, Xu Han, Xuechan Huang, Yukai Huang, Jiajun Chen, Chun Zheng, Xiaolin Fang, Jianhua Yu, Aiwu Wang, Xia Pan, Xiaomin Yu, Tianwang Li","doi":"10.3389/fimmu.2026.2007295","DOIUrl":"https://doi.org/10.3389/fimmu.2026.2007295","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fimmu.2026.1897406.].</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"2007295"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13698831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-educated macrophages promote ferroptosis inhibition in pancreatic cancer via activating the p62-KEAP1-NRF2 pathway.","authors":"Shouying Li, Dongxue Qi, Hanyang Yi, Lina Yang, Tonglei Xu, Wenkai Zhou, Weidong Xu, Ziheng Xu, Haodong Tang, Fangliang Xie, Chunfang Zhang, Xuyang Liang","doi":"10.3389/fimmu.2026.1938077","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1938077","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer is one of the most aggressive and lethal gastrointestinal malignancies, and ferroptosis resistance contributes to chemoresistance. Tumor-educated macrophages(TAMs) are key components of the tumor microenvironment, but whether and how they regulate ferroptosis in pancreatic cancer cells remains largely unknown. This study aimed to investigate the regulatory role of tumor-educated macrophages (TEMs) in pancreatic cancer cell ferroptosis and the underlying molecular mechanism.</p><p><strong>Methods: </strong>TEMs were generated by coculturing THP-1 cells with the pancreatic cancer cell lines PANC1 and CFPAC, and TEM-conditioned medium (TEM-CM) was collected to treat pancreatic cancer cells. Ferroptosis was induced by erastin, and ferroptotic events were assessed by lipid ROS, MDA, iron accumulation, GSH levels, and transmission electron microscopy. RNA sequencing was performed to identify differentially expressed genes. The expression and activity of VEGFR2, C-Raf, ERK1/2, mTOR, LC3, p62, KEAP1, and NRF2 were investigated by treating cells with pharmacological inhibitors (Ki8751, LY3009120, chloroquine, and ferrostatin-1), performing gene knockdown and overexpression, and conducting Western blot co-immunoprecipitation, ubiquitination, and cycloheximide chase assays. <i>In vivo</i> experiments were conducted using an orthotopic mouse model of pancreatic cancer (n = 5 per group).</p><p><strong>Results: </strong>TEM-CM reduced the sensitivity of PANC1 and CFPAC cells to erastin-induced ferroptosis, as evidenced by decreased lipid ROS, MDA, and iron accumulation and increased GSH levels. Neutralization of VEGF, but not IL-10 or TGFβ, significantly reversed the ferroptosis-inhibiting effect of TEM-CM. RNA sequencing identified TM7SF2 as a key mediator. TEM-CM upregulated TM7SF2 mRNA and protein levels, activated mTOR, and suppressed autophagy, leading to p62 accumulation. Accumulated p62 competitively bound KEAP1, disrupted the KEAP1-NRF2 interaction, inhibited NRF2 ubiquitination and degradation, and promoted NRF2 nuclear translocation, thereby upregulating GPX4, HMOX1, and GCLM. Mechanistically, TEM-derived VEGF bound VEGFR2 and activated the C-Raf/ERK1/2 pathway by upregulating TM7SF2, which in turn promoted mTOR phosphorylation. These effects were reversed by TM7SF2 knockdown, VEGF neutralization, VEGFR2 inhibition, or C-Raf inhibition.</p><p><strong>Conclusions: </strong>These findings suggest that TEM-derived VEGF promotes ferroptosis resistance in pancreatic cancer cells through the VEGFR2-TM7SF2-C-Raf/ERK1/2-mTOR-autophagy-p62-NRF2 axis. This axis may represent a potential therapeutic target for overcoming ferroptosis resistance in pancreatic cancer. However, our conclusions are mainly based on <i>in vitro</i> cell models, and further validation in additional cell lines, patient-derived organoids, and <i>in vivo</i> models is warranted.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1938077"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal RNA-seq analysis reveals previously uncharacterized B cell infiltration during late chronic cerebral toxoplasmosis.","authors":"Gabriel Targino, Iasmin Aparecida Cunha Araújo, Anna Laura de Jesus Gomes, Duarte Eduardo Pereira, Valdemir Moreira, Paulo Czarnewski, Neide Maria Silva","doi":"10.3389/fimmu.2026.1885764","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1885764","url":null,"abstract":"<p><p>Chronic toxoplasmosis begins when tachyzoites cross the blood-brain barrier and enter the Central Nervous System (CNS). There, they differentiate into bradyzoites, which persist in tissue cysts. Here, we investigate changes in host gene expression in the mouse brain by RNA sequencing at different time points during chronic toxoplasmosis. We show a conserved gene expression pattern caused by the infection, primarily associated with cytotoxic immune responses against the parasite and neuronal degeneration, regardless of the time point. Surprisingly, we observed that genes associated with B cell function continuously increased over time, whilst cytotoxic responses decreased. Immunoglobulin gene expression and IgA staining showed that B cells were absent from healthy brains. Following infection, they accumulated near penetrating vessels and infiltrated the brain parenchyma. Additionally, these plasma cells produced <i>T. gondii</i>-specific IgA. Our results show a previously unrecognized expansion of brain B cells in late chronic toxoplasmosis.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1885764"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium-dependent conformational transitions and ligand binding regulation of C-reactive protein: a comprehensive review.","authors":"Bin Cheng, Zhi-Xin Yao, Guo-Qiang Wu","doi":"10.3389/fimmu.2026.1963529","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1963529","url":null,"abstract":"<p><p>C-reactive protein (CRP) is a crucial biomarker of inflammation and a primary pattern recognition molecule of the innate immune system. It is predominantly synthesized by hepatocytes and subsequently released into the circulation. The concentration of CRP in plasma can increase significantly, sometimes by up to a thousand-fold, in the presence of infection, inflammation, or tissue damage, making it a widely used clinical indicator of inflammatory status. The distinctive structure of pentameric CRP (pCRP), coupled with the specific functions of its recognition face (B-face) and effector face (A-face) as well as its calcium-dependent ligand recognition, dictates its structural and functional characteristics. This review presents a thorough analysis of the structure and functional surfaces of CRP, focusing on the dual regulatory role of calcium ions (Ca²⁺) in maintaining structural stability and facilitating ligand recognition. It further examines the historical and mechanistic basis of CRP conformational conversion, emphasizing the distinction between Ca²⁺ depletion-induced destabilization and physiologically relevant membrane-associated remodeling that can occur in the continued presence of Ca²⁺. The present review explores the interaction mechanisms of CRP with its ligands, as well as the influence of the microenvironment on CRP's conformational dynamics and functional diversity. This review could provide new prospects for designing targeted drugs according to the structural characteristics of CRP.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1963529"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13698038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR-T-cell therapy for autoimmune neurologic diseases.","authors":"Yunhan Zhao, Yunyu Ding, Congfeng Tang, Zhengrong Wei, Yuqing Fan, Xianhui Hu, Jilong Yi","doi":"10.3389/fimmu.2026.1942249","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1942249","url":null,"abstract":"<p><p>Autoimmune neurologic diseases include multiple sclerosis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune encephalitis, myasthenia gravis, stiff-person syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and related syndromes. The contributions of B cells, plasma cells, and autoantibodies differ substantially across these disorders; however, the B-cell lineage represents a therapeutically actionable target in many of them. Chimeric antigen receptor T-cell therapy, originally developed for hematologic malignancies, offers a potential strategy for deep and potentially durable depletion of pathogenic B-lineage cells and subsequent immune reconstitution. In recent years, CD19, BCMA, dual-target, mRNA CAR-T-cell, and chimeric autoantibody receptor T-cell approaches have generated preliminary clinical or translational evidence, primarily in systemic autoimmune diseases. Clinical evidence in neurologic disorders remains limited and spans myasthenia gravis, NMOSD, MOGAD, multiple sclerosis, autoimmune encephalitis, stiff-person syndrome, and CIDP. This review summarizes the biologic rationale, disease-specific evidence, target selection, safety concerns, and trial-design considerations for CAR-T-cell therapy in autoimmune neurologic diseases. Current evidence supports further investigation of CAR-T cells in selected patients with highly refractory, antibody- or B-cell-driven neuroimmune disorders, but does not establish superiority over existing therapies. However, the field remains dominated by case reports and small early-phase studies, with randomized evidence currently confined to one phase 2b trial in myasthenia gravis. Establishing the risk-benefit profile will require stringent patient selection, disease-specific neurologic monitoring, controlled prospective studies, and long-term follow-up.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1942249"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13700213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial-derived metabolites in cancer: evidence boundaries, immune mechanisms and translational pathways.","authors":"Xuefeng Shi, Shunjun Wang, Wenhao Ouyang","doi":"10.3389/fimmu.2026.1947330","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1947330","url":null,"abstract":"<p><p>Microbial metabolites can suppress or promote tumor development and modify treatment response, but the direction of an effect depends on its chemical identity, anatomical source, concentration and host target. This narrative review critically examines short-chain fatty acids, tryptophan derivatives, secondary bile acids, colibactin, cyclic dinucleotides and microbial activities that alter anticancer drugs. We distinguish individual metabolites from postbiotic preparations, microbial components and enzymes, and separate microbial production from host-microbial co-metabolism. Mechanistic examples include butyrate-dependent chromatin regulation, macrophage aryl hydrocarbon receptor signaling, microbial agonists of STING, colibactin-induced DNA cross-links and bacterial conversion of gemcitabine or irinotecan metabolites. For each, we consider the experimental model, evidence for causality, physiological exposure and limits of human translation. Particular attention is given to apparently conflicting short-chain-fatty-acid findings across checkpoint inhibitors, the conditional effects of dietary fiber, and discordance between experimental drug inactivation and human pancreatic tumor profiling. Human studies support selected biomarker associations and early intervention feasibility, including fecal microbiota transplantation and engineered bacterial delivery, but do not establish a general metabolite-based treatment strategy. We therefore propose a seven-step research framework linking patient sampling, direct quantification and source attribution, causal and functional testing, external biomarker validation, intervention selection, pharmacodynamic monitoring and prospectively defined clinical endpoints. Its contribution is to make the evidence required for each translational decision explicit while distinguishing clinically useful prediction from a causally justified intervention.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1947330"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13698034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal peripheral immune dynamics during anti-programmed cell death 1 neoadjuvant therapy in esophageal squamous cell carcinoma.","authors":"Linpeng Li, Lingwen Meng, Xinru Chen, Jiahui Li, Pengfei Li, Bo Dong, Chengjing Huang, Wei Zhou, Nuan Li, Guodong Sun, Jiawei Li, Guojie Tan, Li Jiang, Dan Tian","doi":"10.3389/fimmu.2026.1917487","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1917487","url":null,"abstract":"<p><strong>Introduction: </strong>Anti-programmed cell death 1 (PD-1)-based neoadjuvant therapy is increasingly used for esophageal squamous cell carcinoma (ESCC), but paired peripheral immune dynamics and their exploratory relationship to response remain incompletely characterized.</p><p><strong>Methods: </strong>We performed a retrospective longitudinal flow-cytometry study of 39 patients with ESCC treated with anti-PD-1-based neoadjuvant therapy, including 20 patients with paired pre-treatment and post-treatment/preoperative peripheral immune profiles. The primary paired analysis tested 75 marker-defined immune features using Wilcoxon signed-rank tests with Benjamini-Hochberg false discovery rate (FDR) correction. Exploratory extensions included response-associated changes in candidate immune features, clinical burden context, baseline-dependence, and public tissue-context bioinformatics. Public tissue data were used only as descriptive tissue context.</p><p><strong>Results: </strong>Four features reached FDR q<0.05 in the primary paired screen: PD-1⁺ CD8 T cells, PD-1⁺ Vδ1 γδ T cells, PD-1⁺ Vδ2 γδ T cells, and CD19⁺ B cells. PD-1-defined features were interpreted as assay-defined detectable PD-1 staining readouts because therapeutic anti-PD-1 receptor occupancy or epitope masking may affect post-treatment staining. CD19⁺ B cells remained the non-PD-1 q<0.05 anchor in the PD-1-excluded paired sensitivity screen. In the pathology-evaluable paired cohort (n=17), no response-stratified candidate reached q<0.05; the change in NKG2D⁺ natural killer (NK) cells was the strongest nominal exploratory and hypothesis-generating signal.</p><p><strong>Discussion: </strong>These data support treatment-associated marker-defined peripheral immune dynamics and generate response-linked hypotheses requiring prospective validation.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1917487"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate dynamics at the <i>Pseudomonas aeruginosa</i>-host interface: bacterial metabolism, host defense, and emerging links to histone lactylation.","authors":"Yi Jian, Zhijie Wu, Yuqiang Liang, Jin Cao, Mei Li, Fashuang Yang, Ke Wang","doi":"10.3389/fimmu.2026.1979311","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1979311","url":null,"abstract":"<p><p>At the <i>Pseudomonas aeruginosa</i>-host interface, lactate is both a host immunometabolic product and a preferred bacterial carbon source. Its local concentration reflects host production, bacterial utilization, transport, and clearance rather than inflammation alone. <i>P. aeruginosa</i> uses D- and L-lactate through stereospecific, conditionally regulated systems. It preferentially consumes lactate in human burn-wound exudate, and this capacity contributes to early intracellular survival in macrophages. Lactate-associated acidity also increases bacterial vesicle release and quinolone signaling, weakening antimicrobial-peptide activity independently of chromatin modification. On the host side, bacterial L-lactate utilization and virulence-factor-associated suppression of epithelial glycolysis lower epithelial lactate and histone H3 lysine 18 lactylation (H3K18la). These changes are linked to disrupted RNA regulation and impaired ciliary clearance. In macrophages, the quorum-sensing signal 2-aminoacetophenone (2-AA) reprograms bioenergetics, autophagy, and lipid metabolism, promoting tolerance and intracellular persistence. A separate hypothesis connecting 2-AA to increased macrophage lactate and H3K18la is supported only by a supplement abstract and requires full-length validation. Histone lactylation is therefore an emerging extension of this biology. This narrative review follows two linked strands: bacterial lactate utilization and lactate-associated changes in host defense. It distinguishes established metabolic effects from proposed lactylation-dependent mechanisms and considers potential therapeutic directions and their trade-offs. These include targeting bacterial lactate utilization, airway acidity, host transport or modification enzymes, and 2-AA-associated tolerance. Any benefit must be assessed against the possibility of supplying bacterial nutrients or worsening host injury.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1979311"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13697012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional single-cell omics in gynecological cancers immunotherapy: from heterogeneity dissection to clinical translation.","authors":"Dong-Mei Li, Kai-Ge Pei, Bo-Wen Yang, Ming-Rong Qie, Jin-Feng Xu, Lan Zhong, Liang Song","doi":"10.3389/fimmu.2026.1981010","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1981010","url":null,"abstract":"<p><p>Ovarian, endometrial, and cervical cancers represent major threats to women's health worldwide. The profound heterogeneity of their immune microenvironments has rendered immune checkpoint blockade (ICB) therapies, particularly PD-1/PD-L1 inhibitors, far less effective than anticipated in gynecological malignancies. Conventional research approaches, constrained by coarse analytical resolution, are insufficient to unravel the underlying mechanisms of this therapeutic shortfall. Functional single-cell omics technologies, including single-cell RNA sequencing, single-cell chromatin accessibility profiling, spatial transcriptomics, and multi-omics integration, have provided a new framework for systematically studying the tumor immune microenvironment across three progressive dimensions: cellular identity, functional state, and spatial localization. This review systematically synthesizes the applications of this technological toolkit in the three major gynecological cancers. It reveals distinct bottlenecks across the three dimensions. In ovarian cancer, the core obstacle lies in the spatial dimension, where cancer-associated fibroblast-mediated physical barriers and pro-angiogenic macrophage subsets together construct a \"spatial exclusion\" microenvironment. In cervical cancer, the principal bottleneck resides in the functional dimension, where HPV status and histological subtype drive a \"functional disability\" phenotype, in which T cells infiltrate but fail to achieve effective activation, with therapy resistance-associated immune evasion clones further exacerbating functional impairment. In endometrial cancer, however, the immune fate is governed by the identity dimension, where molecular subtypes dictate the baseline nature of immune infiltration, and autophagy-related cellular subpopulations may offer new insights into intratumoral heterogeneity. Although single-cell omics has identified immunologically actionable targets with translational potential, including TREM2⁺ macrophages and the LAG-3/TIM-3 dual-target axis, clinical translation remains constrained by technical and biological bottlenecks, including stringent requirements for tissue sample quality, high assay costs, lack of standardized analytical pipelines, and the discordance between transcriptomic profiles and protein-level functionality.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1981010"},"PeriodicalIF":7.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13697309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149265860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}