Frontiers in Immunology最新文献

{"title":"FBXO2 promotes hepatocellular carcinoma progression and sorafenib resistance by targeting USP49 for proteasomal degradation.","authors":"Sirui Hang, Qingqing Wang, Jie Zhang, Yiwei Dong, Bile Hu, Peter Wang, Liu Xu","doi":"10.3389/fimmu.2025.1660034","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1660034","url":null,"abstract":"<p><strong>Introduction: </strong>Hepatocellular carcinoma (HCC) is a highly prevalent and lethal malignancy with limited treatment efficacy due to tumor heterogeneity and the development of drug resistance. Identifying novel molecular mechanisms that drive HCC progression and therapeutic resistance is critical. F-box only protein 2 (FBXO2), an E3 ubiquitin ligase, has recently been implicated in tumorigenesis. However, its role in HCC remains unclear.</p><p><strong>Methods: </strong>We employed CCK-8, EdU, Transwell, and wound healing assays to evaluate the functional role of FBXO2 in HCC cells. Furthermore, Western blotting, immunoprecipitation, <i>in vivo</i> ubiquitination assays, and cycloheximide chase analysis were conducted to investigate the molecular mechanisms through which FBXO2 contributes to tumor progression in HCC.</p><p><strong>Results: </strong>FBXO2 is significantly upregulated in HCC tissues and correlates with poor patient prognosis. Functional assays demonstrated that FBXO2 promotes HCC cell proliferation, migration, and invasion <i>in vitro</i>, while its silencing exerts tumor-suppressive effects. Mechanistically, FBXO2 directly binds to and targets the USP49 for ubiquitin-mediated proteasomal degradation. This degradation decreases USP49 stability and function, thereby enhancing oncogenic potential. Importantly, silencing USP49 reversed the inhibitory effects of FBXO2 knockdown, confirming the FBXO2/USP49 axis as a functional regulator of HCC aggressiveness. Furthermore, FBXO2 depletion significantly enhanced the sensitivity of HCC cells and xenograft tumors to sorafenib treatment.</p><p><strong>Conclusion: </strong>Collectively, our findings establish FBXO2 as a critical modulator of HCC progression and therapeutic resistance via USP49 degradation, highlighting FBXO2 as a promising therapeutic target for overcoming sorafenib resistance in HCC.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1660034"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206264","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":"Bridging the gap: ferroptosis of immune cells in the tumor microenvironment.","authors":"Weijing Wang, Huiyao Li, Shuai Liang, Yani Hu, Junli Ding, Xi Wu, Dong Hua","doi":"10.3389/fimmu.2025.1648432","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1648432","url":null,"abstract":"<p><p>Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly recognized as a pivotal immunomodulatory mechanism within the tumor microenvironment (TME). Beyond its well-established role in tumor cell elimination, emerging evidence reveals that immune cell subsets exhibit distinct susceptibility to ferroptosis, with profound consequences for antitumor immunity. This review systematically delineates the dual and cell-type-specific roles of ferroptosis across innate and adaptive immune populations: while ferroptosis-mediated depletion of immunosuppressive cells potentiates antitumor responses, immunostimulatory cells critically depend on ferroptosis defense pathways to sustain their survival and function-their dysfunction exacerbates immune evasion. We further decode the metabolic and signaling networks that govern immune cell ferroptosis and their dynamic interplay with immunotherapy and engineered nanomaterials. Finally, we critically addressed key challenges in clinical translation, including biomarker development, cell-specific delivery, and design of nanomaterials to minimize off-target effects. By elucidating the immune context-dependence of ferroptosis, this review provides a framework for developing precision therapies that harness ferroptosis-immune crosstalk to improve cancer therapy in the clinic.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1648432"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206297","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":"Post-translational governance of NF-κB in cancer immunity: mechanisms and therapeutic horizons.","authors":"Yue Hong, Ying Fu, Qian Long","doi":"10.3389/fimmu.2025.1627084","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1627084","url":null,"abstract":"<p><p>Nuclear factor-κB (NF-κB) is a central transcriptional orchestrator of inflammation, immune modulation, and tumor progression. Beyond canonical signal transduction, the immunological functions of NF-κB are intricately governed by a spectrum of post-translational modifications (PTMs)-including phosphorylation, acetylation, ubiquitination, and methylation-that fine-tune its activation, nuclear translocation, DNA binding, and transcriptional specificity. In this Review, we explore how these context-dependent PTMs dynamically shape NF-κB's role in cancer immunity: promoting macrophage polarization, controlling antigen presentation by dendritic cells, regulating T cell exhaustion, and sustaining immunosuppressive networks within the tumor microenvironment. We further delineate how PTM-mediated NF-κB signaling interfaces with immune checkpoint expression-particularly PD-L1 and IDO1-and fuels resistance to immunotherapies. Emerging pharmacological strategies targeting NF-κB-modifying enzymes or degradation via PROTACs hold promise to reprogram the immune landscape. By integrating mechanistic insight with translational potential, we position NF-κB's post-translational regulation as a fertile axis for next-generation immunotherapeutic innovation.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1627084"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206168","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":"²²⁵Actinium-armed antibody targeting CCR8⁺ regulatory T cells synergizes with immunotherapy to promote tumor rejection in syngeneic colorectal cancer models.","authors":"Connor Frank, Zhiwen Xiao, Kevin J H Allen, Rubin Jiao, Mackenzie E Malo, Ekaterina Dadachova","doi":"10.3389/fimmu.2025.1662216","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1662216","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) remains a formidable threat to health worldwide. Immunotherapy with immune checkpoint inhibitors results in only a minority of CRC patients experiencing long-term progression-free survival, at the expense of significant autoimmune toxicity. Development of new therapeutics to \"wake up\" the immune system to fight CRC is necessary. Here we investigated for the first time radioimmunotherapy (RIT) directed towards CCR8, a marker of tumor-infiltrating immunosuppressive T-regulatory cells (ti-Tregs) as a method to recover anti-tumor immunity followed by immunotherapy in CRC models.</p><p><strong>Methods: </strong>225Actinium (²²⁵Ac)-labeled anti-CCR8 antibody and anti-CTLA-4 immunotherapy were used to assess their potential synergistic effects in syngeneic murine CRC models CT26 and MC38. The safety of all treatments was assessed through complete blood counts and blood chemistry. ²²⁵Ac-anti-CCR8 RIT-treated tumors were analyzed immunohistochemically for FoxP3 and CCR8 expression while mechanistic studies of tumor-infiltrating lymphocytes were done by flow cytometry.</p><p><strong>Results: </strong>²²⁵Ac-anti-CCR8 RIT alone demonstrated effectiveness in CRC models but dramatic anti-tumor response was observed when it was combined with anti-CTLA-4 immunotherapy. Immunotherapy alone failed to control tumor growth. Tumor immunohistochemistry post ²²⁵Ac-anti-CCR8 RIT showed ablation of CCR8⁺ ti-Tregs while flow cytometry analysis revealed CCR8-specific increased influx of effector CD8⁺ T cells, M1 macrophages and NK cells in comparison with ²²⁵Ac-control antibody.</p><p><strong>Conclusions: </strong>These data demonstrate a synergistic effect of anti-aCCR8 RIT with immunotherapy through enhancement of adaptive and innate anti-tumor responses. Further investigation of anti-CCR8 RIT as a potential cancer-agnostic agent and its combinations with other immunotherapy agents such as anti-PD-1, LAG3 or TIGIT is warranted.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1662216"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206220","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":"An interpretable machine learning model using multimodal pretreatment features predicts pathological complete response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma.","authors":"Xueping Wang, Wencheng Tan, Hui Sheng, Wenjia Zhou, Hailin Zheng, Kewei Huang, Jinfei Lin, Songhe Guo, Minjie Mao","doi":"10.3389/fimmu.2025.1660897","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1660897","url":null,"abstract":"<p><strong>Background: </strong>Although neoadjuvant immunochemotherapy (nICT) has revolutionized the management of locally advanced esophageal squamous cell carcinoma (ESCC), the inability to accurately predict pathological complete response (pCR) remains a major barrier to treatment personalization. We aimed to develop and validate an interpretable machine learning (ML) model using pretreatment multimodal features to predict pCR prior to nICT initiation.</p><p><strong>Methods: </strong>In this retrospective study, 114 ESCC patients receiving nICT were randomly allocated into training (n=81) and validation (n=33) cohorts (7:3 ratio). Predictors of pCR were identified from pretreatment clinical variables, endoscopic ultrasonography, and hematological biomarkers via least absolute shrinkage and selection operator (LASSO) regression. Eight machine learning algorithms were implemented to construct prediction models. Model performance was assessed by area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Shapley Additive Explanations (SHAP) provided feature importance and model interpretability.</p><p><strong>Results: </strong>Following feature selection, 17 variables were incorporated into model construction. The Random Forest (RF) model demonstrated perfect discrimination in the training cohort (AUC = 1.000, sensitivity = 1.000, specificity = 1.000, PPV = 1.000, NPV = 1.000), while maintaining robust predictive ability in the independent validation cohort (AUC = 0.913, sensitivity = 0.733, specificity = 0.889, PPV = 0.846, NPV = 0.800). Decision curve analysis (DCA) confirmed favorable clinical utility. SHAP analysis identified alcohol consumption, circumferential involvement ≥50%, elevated neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), and alanine aminotransferase (ALT) as the key contributors to pCR prediction.</p><p><strong>Conclusions: </strong>We established a clinically applicable, interpretable ML model that accurately predicts pCR to nICT in ESCC by integrating multimodal pretreatment data. This tool may optimize patient selection for nICT and advance precision therapy paradigms.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1660897"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206272","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":"Editorial: Community series in the role of monocytes/macrophages in autoimmunity and autoinflammation, volume II.","authors":"Naoki Iwamoto, Atsushi Kawakami, Sachiko Miyake, Keishi Fujio","doi":"10.3389/fimmu.2025.1699650","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1699650","url":null,"abstract":"","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1699650"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206277","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":"Deciphering the lactylation landscape in glioma: a novel gene signature predicts patient survival and immunotherapy sensitivity.","authors":"Xiaolong Tang, Yi Liu, Congying Yang, Honglan Zhang, Gongming Zhang, Qiao Wang, Sujie Jiang, Xuzhu Gao, Yongshuo Liu, Yanbin Dong","doi":"10.3389/fimmu.2025.1664347","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1664347","url":null,"abstract":"<p><strong>Background: </strong>Glioma, the most prevalent primary brain tumor, takes advantage of lactylation, a metabolic modification linked to tumor behavior and clinical outcomes. Despite its significance, the role of lactylation in the pathogenesis and prognosis of glioma remains underexplored. This study established a lactylation-derived molecular signature to predict survival and response to immunotherapy in glioma.</p><p><strong>Methods: </strong>Leveraging the TCGA glioma cohort, we established a lactylation-related gene (LRG) signature <i>via</i> LASSO and Cox regression analyses, and its prognostic value was validated in independent cohorts. We comprehensively characterized the associations between the LRGs signature and clinicopathological features, tumor immunity (immune infiltration and response to immunotherapy), genomic instability (mutational burden and heterogeneity), tumor stemness, and therapeutic vulnerability. <i>In vitro</i> validation of the oncogenicity of HSPE1 was conducted using the CCK-8, colony formation, transwell, and apoptosis assays in U87 and U251 glioma cells.</p><p><strong>Results: </strong>A four-gene lactylation signature (KIF2C, CALD1, HSPE1, and IFI16) was identified. Elevated LRGs score were correlated with advanced tumor grade, poor prognosis, and reduced response to immunotherapy. Patients in the LRGs-high group exhibited adverse clinicopathological features, including advanced age, higher WHO grade, IDH wild-type status, and 1p/19q non-codeletion. The nomogram model based on the LRGs score exhibited robust prognostic accuracy (C-index = 0.860). LRGs-related genes were enriched in immune regulatory pathways, such as cytokine signaling and interferon-γ response pathways. The LRGs-high group displayed increased infiltration of immunosuppressive cells, such as M2 macrophages, MDSCs, and CAFs, and distinct genomic instability profiles. Crucially, HSPE1 knockdown significantly suppressed the proliferation and invasion of glioma cell lines.</p><p><strong>Conclusions: </strong>We defined a novel LRGs signature integrating metabolic and immune dysregulation in glioma. This signature served as an independent predictor of prognosis and immunotherapy. Furthermore, we identified HSPE1 as a critical driver of glioma progression.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1664347"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206308","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":"No evidence of MMR induced trained immunity to prevent SARS COV2: results from a multi-centre RCT.","authors":"Sinead Delany-Moretlwe, Hakim-Moulay Dehbi, Izukanji Sikazwe, George Kyei, Kwadwo Koram, Erik Dubberke, Noluthando Mwelase, Dominic Hague, Linda-Gail Bekker, Linda Yun, Annalene Nel, Leon du Toit, Bruce Biccard, Katherine Gill, Chikumbutso Chipeta, Kathryn T Mngadi, Limakatso Lebina, Reshmi Dassaye, Villeshni Asari, Samantha H Fry, Edwin Turton, Khatija Ahmed, Kwadwo Kusi, Susan Adu-Amankwah, Roma Chilengi, Joyce Chinyama Chilekwa, Laurence Lovat, Dermot McGuckin, Emilia Caverly, Mary Politi, Ben Swan, Anne DeSchryver, Sherry McKinnon, Ananya Gupta, Gemma Jones, Nicholas Freemantle, Shabaana Khader, Helen Rees, Mihai G Netea, S Ramani Moonesinghe, Michael S Avidan","doi":"10.3389/fimmu.2025.1588190","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1588190","url":null,"abstract":"<p><strong>Background: </strong>Measles-containing vaccines (MCV), by training innate immune cells, are hypothesized to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19).</p><p><strong>Methods: </strong>In this international, double-blind, placebo-controlled trial, we randomly assigned adults, 18 years and older, to receive MCV or saline. The primary outcome was polymerase chain reaction (PCR) confirmed symptomatic COVID-19, up to 60 days after intervention. Secondary outcomes were PCR-confirmed symptomatic COVID-19 and serologically confirmed SARS-CoV-2 infection, up to 150 days after intervention.</p><p><strong>Results: </strong>Of 3411 randomised participants, the modified intention-to-treat population included 1607 in the MCV and 1545 in the saline group. The estimated risk of symptomatic COVID-19 by 60 days was 1.5% in the MCV and 1.2% in the saline group (risk difference, 0.3 percentage points, 95% CI, -0.5 to 1.1; p=0.52). At 150 days, these percentages were 4.1% (65/1585) and 4.1% (64/1544) in the MCV and saline groups, respectively (risk difference, 0.04 percentage points, 95% CI, -1.4 to 1.3; p=0.95). Based on serology results available at 0 and 150 days, 10.6% (100/945) of participants in the MCV and 10.3% (98/951) in the saline group had infection with SARS-CoV-2 over the course of the trial (risk difference, 0.3 percentage points, 95% CI, -2.6 to 3.1; p=0.84). Three patients were hospitalised with COVID-19 disease in the MCV and one in the saline group.</p><p><strong>Conclusions: </strong>Administering MCVs to stimulate trained immunity did not prevent COVID-19 or SARS-CoV2 infection. Stimulating trained immunity might not be useful for preventing respiratory illness during future pandemics.</p><p><strong>Clinical trial registration: </strong>https://clinicaltrials.gov/, identifier NCT04333732.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1588190"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206199","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":"Efficacy and safety of immune checkpoint inhibitors for advanced squamous non-small cell lung cancer: a systematic review and network meta-analysis.","authors":"Na Liu, Baowanze Zhang, Jiali He, Su Li","doi":"10.3389/fimmu.2025.1635757","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1635757","url":null,"abstract":"<p><strong>Objective: </strong>Significant efficacy heterogeneity exists between first- and second-line immunotherapy regimens for advanced squamous non-small cell lung cancer (SqNSCLC), but most regimens lack directly comparable clinical trial evidence, resulting in unclear prioritization. This analysis identifies optimal treatment strategies by evaluating differences in efficacy across immune checkpoint inhibitors (ICIs).</p><p><strong>Methods: </strong>We search through comprehensive databases, including PubMed, Embase, the Cochrane Library and the Clinical Trials Database. Traditional meta-analysis was done using Stata 15.0, while Bayesian-framework network meta-analysis was implemented with R's GEMTC package via Markov chain Monte Carlo simulation. Subgroup analyses were performed for different PD-L1 expression levels, number of treatments, ethnic groups, and smoking history.</p><p><strong>Results: </strong>We included 25 randomized controlled trials. Immune-related therapy can provide significant benefit relative to chemotherapy alone in advanced SqNSCLC. Compared with chemotherapy, except for ipilimumab+chemo [HR = 0.92,95%CI: (0.59-1.40)], atezolizumab+chemo [HR = 0.88, 95%CI: (0.56-1.40)], and durvalumab+chemo [HR = 0.84, 95% CI: (0.52-1.40)], durvalumab+ tremelimumab+chemo [HR = 0. 88, 95% CI: (0.54-1.40)], which significantly improved overall survival(OS). Cemiplimab [HR = 0.48, 95% CI: (0.34-0.67)] showed the best OS benefit. Compared with chemotherapy, all immunotherapies significantly improved progression-free survival (PFS) except for ipilimumab+chemo [HR = 0.87, 95% CI: (0.75-1.00)]. Sugemalimab+chemo provided the best survival benefit [HR = 0.34, 95% CI: (0.24-0.48)]. For PD-L1≥50% tumors, penpulimab showed excellent OS and PFS; for PD-L1 1-49% tumors, pembrolizumab+chemo and camrelizumab+chemo achieved the best OS and PFS, respectively; for PD-L1≥1% tumors, the tislelizumab+chemo and camrelizumab+chemo showed the best OS and PFS results, while for tumors with PD-L1 <1%, both nivolumab and serplulimab+chemo provided significant survival benefit. In Asian patients, patients treated with pembrolizumab or pembrolizumab + chemotherapy had favorable OS and PFS benefits. In non-Asian patients, there was also favorable OS and PFS benefit with cemiplimab. For former/current smokers, pembrolizumab+chemotherapy and camrelizumab+chemotherapy had significant OS and PFS benefit, but most immunotherapies did not improve OS and PFS in never smokers. Camrelizumab+chemo [OR = 3.5, 95% CI: (2.3-5.3)] had the best overall response rate (ORR) benefit. Ipilimumab+chemo had the highest incidence of adverse events (AEs) [OR = 2.0, 95% CI:(1.5-2.7)].</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/prospero/, identifier CRD420251027447.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1635757"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206248","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":"Th17-associated cytokine gene hypomethylation reflects epigenetic dysregulation in graves' disease.","authors":"Yanfei Jiang, Kaida Mu, Zhaowei Huang, Xinwei Zhang, Yalin Wang, Wenyu Xu, Ronghua Song, Jinan Zhang","doi":"10.3389/fimmu.2025.1635883","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1635883","url":null,"abstract":"<p><strong>Introduction: </strong>Graves' disease (GD) is an organ-specific autoimmune disorder characterized by the presence of thyroid-stimulating hormone receptor autoantibodies (TRAb), leading to hyperthyroidism. While genetic and environmental factors contribute to GD pathogenesis, the role of epigenetic mechanisms, particularly in regulating Th17-associated cytokines, remains poorly understood.</p><p><strong>Methods: </strong>This study aimed to characterize the promoter methylation profiles of IL17, IL21, and IL22 in GD patients, evaluate their diagnostic potential, and explore correlations with clinical parameters. Targeted bisulfite sequencing was performed on peripheral blood mononuclear cells from 60 GD patients, including newly diagnosed and refractory individuals, and 60 matched healthy controls.</p><p><strong>Results: </strong>Significant hypomethylation at IL17, IL21, and IL22 promoter regions was observed in GD patients compared with controls (P = 2.5 × 10⁻⁷), with partial methylation restoration in refractory cases. Four specific CpG sites were identified as potential biomarkers, demonstrating good diagnostic performance with area under the curve (AUC) values exceeding 0.7, including chr4_123542549_R (AUC = 0.754) and chr12_68647247_R (AUC = 0.752). These sites were associated with elevated TRAb (OR = 4.00, P = 0.02) and FT4 levels (OR = 0.29, P = 0.02), respectively.</p><p><strong>Discussion: </strong>Our findings highlight Th17-related epigenetic dysregulation as a key feature of GD and support the potential of methylation markers for diagnostic and therapeutic monitoring applications.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1635883"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206186","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}