Frontiers in Immunology最新文献

{"title":"Spatial organization of intratumoral microbiome and regional tumor immunity.","authors":"Jhommara Bautista, Andrés López-Cortés","doi":"10.3389/fimmu.2026.1961794","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1961794","url":null,"abstract":"<p><p>Solid tumors are spatially heterogeneous ecosystems in which immune recruitment, anatomical access, functional competence, stromal organization, vascularization and physicochemical conditions vary across regions. The conventional \"hot-cold\" dichotomy therefore obscures the coexistence of immune-inflamed, immune-excluded, immune-suppressed and immune-desert territories within the same lesion. Intratumoral microorganisms add a second layer of heterogeneity, yet microbial signals are often interpreted from bulk abundance without resolving their location, host-cell compartment, viability or functional state. The distinct contribution of this review is the integration of spatial microbial signals with regional immune ecotypes defined independently from microbial presence. Immune-inflamed, immune-excluded, immune-desert, and immune-suppressed regions are assigned from host features of immune recruitment, access to malignant cells, functional competence, and multicellular organization before microbial localization, cellular compartmentalization, and biological state are considered. We examine how intracellular microbial material in malignant cells, phagocyte-associated signals, extracellular biofilms and bacteria-positive microniches may differentially engage HLA-mediated antigen presentation, cGAS-STING or direct STING signaling, TLR-MyD88-TRAF6 pathways, dendritic-cell and natural-killer-cell circuits, and myeloid, stromal and metabolic programs. Depending on microbial identity, burden, persistence and cellular address, these interactions may support cytotoxic immunity or promote chronic inflammation, suppressive myeloid accumulation, neutrophil extracellular traps, regulatory T-cell expansion, T-cell dysfunction and matrix-associated exclusion. We further assess physicochemical selection, microbial metabolism, metastatic persistence, treatment-associated remodeling and spatial multi-omic strategies for defining clinically relevant immunomicrobial niches. Current evidence remains limited by low biomass, contamination risk, incomplete source attribution, cross-sectional sampling and scarce causal validation. Future studies should combine multiregional and longitudinal sampling with orthogonal microbial detection, cell-resolved host profiling, viability and activity measurements, and controlled perturbation. This model reframes tumors as mosaics of regional immune ecotypes in which spatially localized microbial signals acquire context-dependent biological meaning.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1961794"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227698","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":"Integrative multi-omics analysis reveals a membrane tension signature associated with tumor-stroma crosstalk in hepatocellular carcinoma.","authors":"Pengfei Zhu, Pengcheng Zhu, Zijuan Zhu, Gaozhong Bian, Yungang Liu, Qifan Yang, Peipei Luo","doi":"10.3389/fimmu.2026.1978174","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1978174","url":null,"abstract":"<p><strong>Background: </strong>Dysregulated membrane tension (MT) drives tumor cell migration, invasion, and immune evasion, yet the prognostic value of MT-related genes (MTRGs) in hepatocellular carcinoma (HCC) remains unclear.</p><p><strong>Methods: </strong>We integrated transcriptomic and clinical data from TCGA, ICGC, and GEO. A three-gene MTRG prognostic signature was developed through univariate and LASSO-Cox regression, and validated using Kaplan-Meier analysis, time-dependent ROC curves, and calibration plots. Functional enrichment, immune infiltration, tumor mutational burden, and immunotherapy response was predicted using the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Single-cell and spatial transcriptomics were used to investigate the mechanistic role of CFL1 in tumor-stroma crosstalk.</p><p><strong>Results: </strong>The signature (CFL1, CRTC2, SRGAP2) stratified HCC patients into high- and low-risk groups with distinct overall survival (OS). High-risk tumors showed coordinated activation of MT and ECM-remodeling pathways alongside an immunosuppressive microenvironment. In silico analyses suggested that CFL1-high tumor cells may transmit MDK signals to fibroblasts (via SDC2, NCL, and ITGA4-ITGB1) and to T cells (via NCL). Spatial transcriptomics confirmed predominant CFL1 enrichment in stromal compartments. The signature was an independent prognostic factor, and the nomogram showed promising clinical utility.</p><p><strong>Conclusions: </strong>This three-gene MTRG-associated signature is associated with predicted immunotherapy response based on computational analysis in HCC. Our results suggest a potential link between biophysical MT and tumor stroma co evolution and represent a potential therapeutic direction warranting further experimental validation.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1978174"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223746","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":"The blood-brain tumor barrier as a spatial immune checkpoint in glioblastoma: leukocyte entry, perivascular retention, and therapeutic implications.","authors":"Fangbo Lin","doi":"10.3389/fimmu.2026.1957858","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1957858","url":null,"abstract":"<p><p>Glioblastoma (GBM) combines heterogeneous vascular dysfunction with a predominantly myeloid immune landscape. This Mini Review focuses on a specific problem: vascular permeability is not equivalent to productive leukocyte access. Entry requires endothelial capture, chemokine-guided arrest, transendothelial migration, release from perivascular sites, intratumoral dispersion, target recognition, and sustained effector function. Human tissue and spatial studies show regionally distinct neurovascular and myeloid states, whereas much of the causal evidence for trafficking and retention remains preclinical. We therefore distinguish published observations from a hypothesis-generating model in which the blood-brain tumor barrier (BBTB) and perivascular myeloid niche can act as coupled but separable checkpoints. The main conceptual advance is not the already recognized heterogeneity of the BBTB, but the argument that leakage-based imaging should not be used as a surrogate for immune-cell entry and that each trafficking stage requires its own pharmacodynamic readout. We summarize regional BBTB states, differential lymphoid and myeloid access, and selected strategies-vascular normalization, myeloid reprogramming, local cell delivery, and focused ultrasound-while emphasizing their evidence limits. Clinical translation will require spatially registered human sampling, explicit model provenance, and tests that can reject individual components of the framework.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1957858"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223872","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":"Multimodality salvage treatment incorporating ivonescimab plus chemotherapy for EGFR-mutated NSCLC with leptomeningeal metastases after dose-escalated third-generation EGFR-TKI failure: a retrospective study.","authors":"Qichao Wu, Lei Qiu, Juan An, Weiran Xu, Xiaosheng Ding, Hui Shi, Yichun Hua, Xixi Zheng, Yijia Guo, Beihe Cao, Xiaoyan Li","doi":"10.3389/fimmu.2026.1973923","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1973923","url":null,"abstract":"<p><strong>Background: </strong>Leptomeningeal metastasis (LM) is among the most devastating modes of progression in EGFR-mutated non-small cell lung cancer (NSCLC). Although dose escalation of third-generation EGFR-TKIs has been an important central nervous system (CNS)-directed salvage strategy, therapeutic options after progression on this intensification approach remain limited.</p><p><strong>Methods: </strong>This single-center retrospective study included consecutive patients treated between September 2024 and December 2025. Eligible patients were adults (≥18 years) with histologically confirmed lung adenocarcinoma, a documented EGFR mutation, and LM diagnosed by gadolinium-enhanced MRI or positive cerebrospinal fluid (CSF) cytology. Patients received ivonescimab plus chemotherapy after documented intracranial or extracranial progression on a dose-escalated third-generation EGFR-TKI regimen used for LM management, with or without concurrent CSF-directed therapy. Ivonescimab was given intravenously at 20 mg/kg every 3 weeks with chemotherapy selected according to prior treatment and clinical status. The primary endpoints were overall survival (OS) and LM progression-free survival (LM-PFS).</p><p><strong>Results: </strong>Of 517 screened patients, 33 initiated ivonescimab plus chemotherapy and comprised the overall treated cohort. Concurrent intrathecal or intraventricular chemotherapy was administered to 29 of 33 patients (87.9%). The median age was 61 years (IQR 56-62); 24 (72.7%) were female; 24 (72.7%) had baseline ECOG performance status of 2-3. The median number of prior therapy lines was 4 (IQR 3-6). At a median follow-up of 8.28 months, median OS was 8.54 months (95% CI 5.75-14.32), median LM-PFS was 6.54 months (95% CI 3.42-11.86), and median systemic PFS was 4.83 months (95% CI 2.79-7.56). Three-month treatment persistence was 64.4% (95% CI 44.9-78.6). Among 29 patients evaluable for LM response, 6 achieved a response, yielding an LM response rate of 20.7% (95% CI 8.0-39.7) and an LM disease control rate of 82.8% (95% CI 64.2-94.2). Among 31 patients with evaluable safety documentation, grade ≥3 treatment-related adverse events occurred in 14 (45.2%), most commonly hematologic toxicities. No permanent ivonescimab discontinuation due to toxicity was documented.</p><p><strong>Conclusions: </strong>This cohort provides real-world outcome data for patients with EGFR-mutated NSCLC and LM receiving multimodality salvage treatment incorporating ivonescimab plus chemotherapy after dose-escalated third-generation EGFR-TKI failure.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1973923"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223897","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":"Case Report: Narcolepsy associated with anti-Ma2 antibody positivity.","authors":"Yefan Lv, Hui Lv, Yike Huang, Xiaoyan Long, Jinxia Zhou","doi":"10.3389/fimmu.2026.1942979","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1942979","url":null,"abstract":"<p><strong>Background: </strong>Several intraneuronal antibodies have been identified in association with paraneoplastic encephalitis, including anti-Ma and anti-Yo antibodies. There is a pure case of narcolepsy associated with anti-Ma2 antibody positivity with concomitant anti-Yo antibody.</p><p><strong>Case presentation: </strong>We report a 42-year-old male patient who presented with recurrent cataplexy as the primary and dominant symptom without typical hyperphagia in the early stages of narcolepsy associated with anti-Ma2 antibody positivity. Despite extensive screening, no underlying malignancy was detected over a 3-year disease duration. The patient exhibited significant clinical improvement following immunotherapy at the beginning.</p><p><strong>Conclusions: </strong>This is a rare report of an isolated clinical manifestation of narcolepsy associated with anti-Ma2 antibody positivity with concomitant anti-Yo antibody. This case reminds clinicians to notice that cataplexy could be the only early symptom of narcolepsy associated with anti-Ma2 antibody positivity with concomitant anti-Yo antibody, which can easily lead to misdiagnoses. Autoimmune mechanisms may play an important role in the pathogenesis of narcolepsy associated with anti-Ma2 antibody positivity, and prompt immunotherapy offers a promising approach for its management.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1942979"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223904","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":"Endoplasmic reticulum stress in autoimmune skin diseases: immune activation, cutaneous cell damage, and therapeutic advances.","authors":"Jiaxi Qiao, Jia Chen, Jinbo Chen, Liuqing Chen","doi":"10.3389/fimmu.2026.1980040","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1980040","url":null,"abstract":"<p><p>Endoplasmic reticulum stress (ERS) arises when the protein-folding load, or perturbations in calcium and redox homeostasis, outpace the adaptive capacity of the endoplasmic reticulum (ER). The unfolded protein response (UPR) initially reduces secretory load and restores proteostasis. Persistent stress can redirect the same pathways toward inflammatory signaling, altered antigen processing, and potentially immunogenic cell death. We term this context-dependent transition ERS-immune tolerance breaking, and propose it as a unifying framework for understanding how unresolved ERS may contribute to loss of cutaneous immune homeostasis. It is especially relevant in skin, where keratinocytes and melanocytes encounter ultraviolet radiation and oxidative injury while infiltrating immune cells face large biosynthetic demands. Evidence from vitiligo, pemphigus vulgaris, psoriasis, lupus erythematosus, and systemic sclerosis links dysregulated IRE1α, PERK, and ATF6 signaling to target-cell damage and immune amplification. In this review, we evaluate this evidence with particular attention to disease-specific mechanisms and the strength of causal inference supporting a pathogenic role for ERS. The case for a pathogenic role is strongest when ERS has been manipulated in defined cell types or experimental models; associations based only on UPR markers in lesions remain harder to interpret. Therapeutic studies also caution against treating the UPR as a uniformly harmful pathway. Intervention will probably need to preserve adaptive proteostasis while limiting the pathogenic output that predominates in a particular cell population and disease phase.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1980040"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223920","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":"The role and mechanism of macrophage-to-myofibroblast transition in fibrotic diseases.","authors":"Hua Guo, Xiao Xiao Tang","doi":"10.3389/fimmu.2026.1919029","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1919029","url":null,"abstract":"<p><p>Fibrosis is a pathological process primarily characterized by excessive deposition of extracellular matrix (ECM), which leads to disruption of tissue architecture and progressive loss of organ function, serving as a key pathological basis for various chronic diseases. Recent studies have revealed that, in addition to conventional sources, macrophages can directly differentiate into ECM-producing myofibroblasts through a process termed macrophage-to-myofibroblast transition (MMT), thereby actively participating in fibrogenesis. The concept of MMT was initially proposed in the context of renal fibrosis and has since been validated in multiple organs, including the kidney, heart, lung, liver, and retina. This review aims to summarize the role of MMT in fibrotic diseases and to elucidate the mechanism underlying MMT and fibrosis progression. Unlike prior reviews that predominantly focus on MMT within individual organs or separately delineate their molecular pathways, this review adopts a cross-organ perspective to systematically identify conserved mechanisms, tissue-specific regulatory networks, and translational challenges of MMT across fibrotic diseases.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1919029"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227686","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: Astrocyte-derived HMGB1 compromises the integrity of the blood-brain barrier through the CaM/CaMKII/AQP4 pathway and the protective function of trifluoperazine.","authors":"Song-Song Zou, Li-Li Chen, Min Cui","doi":"10.3389/fimmu.2026.1987139","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1987139","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fimmu.2026.1852083.].</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1987139"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227708","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":"Immunomodulatory strategies for ex vivo immune cell expansion in adoptive cell therapy: translational and regulatory considerations for clinical manufacturing.","authors":"Weng Wan Chan, Estella Zhi Yu Lim, Deepak Choudhury","doi":"10.3389/fimmu.2026.1861621","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1861621","url":null,"abstract":"<p><p>Ex vivo expansion is a fundamental yet challenging step in the manufacturing of adoptive cell therapies (ACT), as therapeutic success relies on generating enough functional immune cells while maintaining their phenotype, metabolic fitness, and persistence. This review provides a comprehensive overview of immunomodulatory strategies designed to enhance cell yield during ex vivo expansion, categorizing them into cell-intrinsic and cell-extrinsic approaches. Cell-intrinsic strategies, including gene editing and gene transfer technologies, enable precise modulation of survival pathways, proliferation, metabolic state, and resistance to exhaustion. These tools support the production of more potent and durable immune cell products. In contrast, cell-extrinsic strategies shape immune cell behavior through cytokine supplementation, checkpoint blockade, nutrient and metabolic modulation, feeder cell systems, synthetic activation platforms, and biophysical cues such as oxygen tension and bioreactor-controlled environments. Together, these strategies provide coordinated signals that direct activation, differentiation, and persistence during expansion in culture. The review also highlights key regulatory considerations, including distinctions between genetically and non-genetically modified products, risk assessments associated with human and animal-derived materials, ancillary material qualification, and process scalability for clinical translation. By integrating biological, engineering, and regulatory perspectives, this paper outlines principles for scalable immunomodulation platforms designed with regulatory considerations in mind to advance next-generation ACT manufacturing.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1861621"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227759","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":"AKNA serves as a prognostic biomarker and restrains endometrial cancer progression via STING activation and macrophage reprogramming.","authors":"Yuan Tu, Lingya Xu, Chengfan Tian, Yuanling Shi, Jiaxin Yu, Chunxia Gong, Tianyu Peng, HangKun Yu, Rui Yuan, Peng Jiang","doi":"10.3389/fimmu.2026.1905624","DOIUrl":"https://doi.org/10.3389/fimmu.2026.1905624","url":null,"abstract":"<p><strong>Background: </strong>AKNA, an AT-hook transcription factor, plays a critical role in cancer development. However, its prognostic value and biological function in endometrial cancer (EC) remain unclear.</p><p><strong>Methods: </strong>To systematically investigate AKNA in EC, we integrated multi-omics data (The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and single-cell transcriptomics), dual independent clinical cohorts (TCGA-UCEC dataset and two institutional cohorts), and <i>in vitro</i>/<i>in vivo</i> experimental models. Immunohistochemistry, RT-qPCR and Western blotting were used for expression validation. Functional assays, including lentiviral-mediated AKNA knockdown/overexpression, CCK-8, scratch-wound, Transwell, flow cytometry, and colony formation assays were conducted to assess the effects of AKNA modulation on proliferation, migration, invasion, epithelial-mesenchymal transition, chemosensitivity and macrophage polarization. Mechanistically, chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), ChIP-qPCR, and dual-luciferase reporter assays were employed to define the transcriptional regulation of stimulator of interferon genes (STING) by AKNA. A prognostic nomogram integrating AKNA expression with clinicopathological features was developed and externally validated in independent cohorts.</p><p><strong>Results: </strong>AKNA was significantly downregulated in EC tissues compared with normal endometrium, which was associated with advanced International Federation of Gynecology and Obstetrics stage, aggressive histological subtypes, and poor prognosis. AKNA knockdown promoted EC cell proliferation, migration, invasion, and epithelial-mesenchymal transition, while enhancing M2 macrophage polarization and reducing sensitivity to paclitaxel and potentially compromising anti-tumor innate immunity. Conversely, AKNA overexpression or STING activation by cyclic GMP-AMP reversed these malignant phenotypes. Mechanistically, AKNA directly bound to the STING promoter and transcriptionally activated STING, thereby inducing TANK-binding kinase 1 and interferon regulatory factor 3 phosphorylation. The nomogram combining AKNA with clinicopathological features demonstrated high accuracy in predicting EC recurrence and outperformed single-variable models in both training and validation cohorts.</p><p><strong>Conclusions: </strong>AKNA deficiency promotes EC progression by transcriptionally suppressing STING and driving M2 macrophage polarization. AKNA serves as a robust prognostic biomarker and predictive indicator for chemotherapy and innate immune modulation, offering a promising therapeutic target for precision treatment of EC.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"17 ","pages":"1905624"},"PeriodicalIF":7.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223852","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}