International immunopharmacology最新文献

{"title":"Reply to: “Advancing insights into psoriasis: From pathogenesis to current and emerging therapies”","authors":"Martim Luz , Tiago Torres","doi":"10.1016/j.intimp.2025.115550","DOIUrl":"10.1016/j.intimp.2025.115550","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115550"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine-1-phosphate signaling in respiratory diseases: mechanisms and therapeutic perspectives","authors":"Juan Yang ,&nbsp;Wenyi Zhong ,&nbsp;Qiongqiong Li ,&nbsp;Wei Zhang ,&nbsp;Wenyan Lin ,&nbsp;Xianming Fan ,&nbsp;Yijing He ,&nbsp;Ning Ma","doi":"10.1016/j.intimp.2025.115578","DOIUrl":"10.1016/j.intimp.2025.115578","url":null,"abstract":"<div><div>Sphingosine-1-phosphate (S1P) is a pivotal bioactive sphingolipid functioning as both a structural membrane component and a signaling mediator. It orchestrates diverse physiological and pathological processes including cellular proliferation, migration, differentiation, and immune regulation. The biological efficacy of S1P is controlled by metabolic networks that coordinate its biosynthesis, transport, and degradation to maintain intra/extracellular homeostasis and to activate cell surface S1P receptors (S1PRs) to initiate downstream signaling. Contemporary research increasingly has increasingly revealed the multifaceted roles of S1P signaling in respiratory pathologies, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary malignancies, and especially infectious lung diseases such as COVID-19 and influenza. Particularly, S1P levels are significantly correlated with the severity and prognosis of the disease. These findings indicate that pharmacological modulation of the S1P signaling axis, through sphingosine kinase (SPHK1/2) inhibition, S1P lyase (SPL) inhibition, or the S1PR modulation represents a promising therapeutic approach. However, incomplete understanding of the S1P signaling mechanisms presents significant challenges for clinical applications. This review systematically consolidates recent advances in S1P signaling research in respiratory medicine, with particular emphasis on delineating cellular and molecular mechanisms and evaluating the translational potential of targeted therapeutics.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115578"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salvianolic acid B inhibits melanoma via dual modulation of glycolysis and NK/T cell immunity","authors":"Yongli Zhang ,&nbsp;Cang Li ,&nbsp;Jianxin Chen","doi":"10.1016/j.intimp.2025.115567","DOIUrl":"10.1016/j.intimp.2025.115567","url":null,"abstract":"<div><div>Melanoma is a highly aggressive malignancy, and resistance to immune checkpoint inhibitors (ICIs) remains particularly pronounced in acral and mucosal subtypes among Chinese patients. A key driver of this resistance is glycolysis-driven lactate accumulation, which fosters an immunosuppressive tumor microenvironment (TME). Salvianolic acid B (Sal B), a natural compound derived from <em>Salvia miltiorrhiza</em>, has shown therapeutic promise, but its anti-melanoma mechanism remains largely undefined. Here, we used network pharmacology to predict the potential core targets of Sal B in melanoma, and validated the antitumor effect of Sal B in A375 cells and xenograft mouse models. Sal B markedly inhibited cell proliferation, migration, and invasion, induced G2/M cell cycle arrest and apoptosis, and suppressed glycolytic activity. In vivo, Sal B significantly reduced tumor growth, and transcriptomic profiling revealed upregulation of immune-related genes, including those in the TNF pathway. Consistently, Sal B treatment increased the proportions of NK and CD8⁺ T cells, indicating that it may reshape the TME through metabolic reprogramming and immune activation. Compared to single-agent ICIs, Sal B offers dual metabolic-immune modulation, providing a new avenue for integrative immunotherapy in refractory melanoma prevalent in Chinese patients. Its natural origin and multi-target features may further reduce toxicity and enhance therapeutic precision, supporting the development of personalized treatment strategies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115567"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMP9 suppresses TNF-α-induced inflammatory response in fibroblast-like synoviocytes through Smad pathway in rheumatoid arthritis","authors":"Biao Song ,&nbsp;Dan-tong Sun ,&nbsp;Yong-feng Cheng ,&nbsp;Qing-qing Xia ,&nbsp;Xiao-feng Li ,&nbsp;Zong-wen Shuai ,&nbsp;Jun Li","doi":"10.1016/j.intimp.2025.115544","DOIUrl":"10.1016/j.intimp.2025.115544","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) represents a chronic autoimmune disease in which fibroblast-like synoviocytes (FLS) are pivotal contributors to disease pathogenesis. Reportedly, BMP9 inhibits the proliferation and migration of FLS in adjuvant-induced arthritis (AIA). Herein, we examined whether BMP9 suppresses the inflammatory response of RA FLS. The experimental results demonstrated a significant downregulation of BMP9 in RA synovial tissues, exhibiting an inverse correlation with TNF-α expression patterns. BMP9 silencing exacerbated TNF-α-mediated inflammatory responses in RA FLS, leading to substantial upregulation of IL-1β, IL-6, CXCL2, CXCL3, and CXCL5 expression levels. Conversely, BMP9 overexpression attenuated the inflammatory responses following stimulation with TNF-α and blocked the expression of IL-1β, IL-6, CXCL2, CXCL3, and CXCL5. Furthermore, BMP9 overexpression differentially regulated Smad signaling pathways by downregulating p-Smad2/3 while enhancing p-Smad1/5/9 activation. These findings demonstrate that BMP9 exerts anti-inflammatory effects in RA FLS by modulating Smad-dependent signaling pathways.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115544"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B cells in metabolic dysfunction-associated steatotic liver disease (MASLD): From mechanisms to therapeutic exploration","authors":"Leyao Jia ,&nbsp;Xue Bai ,&nbsp;Wenjing Ni ,&nbsp;Shengxia Yin ,&nbsp;Junping Shi ,&nbsp;Yongfeng Yang ,&nbsp;Jie Li","doi":"10.1016/j.intimp.2025.115553","DOIUrl":"10.1016/j.intimp.2025.115553","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30 % of the global population and has become a major cause of chronic liver disease, encompassing progressive conditions like metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and related hepatocellular carcinoma (HCC). Adaptive immunity, particularly B cells, plays a critical role in MASLD pathogenesis. Different B cell subsets, including B1, B2 cells, and regulatory B cells (Bregs), participate in disease progression through various mechanisms, such as cytokine secretion, antibody production, and crosstalk between adipose tissue and the liver, influencing inflammation, insulin resistance, and fibrosis development. Key factors like B cell-activating factor (BAFF) and signaling pathways including toll-like receptor (TLR) signaling are involved in B cell activation and their pathogenic effects. Emerging therapeutic strategies target B cell migration or signaling pathways. This review summarizes current evidence on B cells' multifaceted roles in MASLD progression, focusing on their activation mechanisms in MASH-related fibrosis and exploring potential B cell-targeted therapeutic prospects.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115553"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of ferroptosis-related genes as diagnostic biomarkers and therapeutic targets in sorafenib-resistant HCC via machine learning and experimental validation","authors":"Jinrui Zhang ,&nbsp;Wenhan Geng ,&nbsp;Haojin Sun ,&nbsp;Jian Chen ,&nbsp;Yumei Fan,&nbsp;Ke Tan","doi":"10.1016/j.intimp.2025.115557","DOIUrl":"10.1016/j.intimp.2025.115557","url":null,"abstract":"<div><div>Liver cancer, particularly hepatocellular carcinoma (HCC), remains a significant health burden with poor survival rates due to late diagnosis and limited treatment options. Sorafenib, a multi-kinase inhibitor, is the standard first-line therapy for advanced HCC, but long-term use often leads to drug resistance. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a crucial target in cancer therapy, showing potential to enhance treatment efficacy and overcome drug resistance. Previous studies have demonstrated that sorafenib triggers ferroptosis in HCC cells and that ferroptosis plays a significant role in the development of sorafenib resistance. However, the intricate interplay between ferroptosis and sorafenib resistance remains poorly understood, hampering the development of effective therapeutic strategies. Our study focuses on the intricate interplay between ferroptosis and sorafenib resistance in HCC. Using the GSE109211 dataset, we identified differentially expressed ferroptosis-related genes associated with sorafenib resistance. Notably, these genes stratified sorafenib-resistant HCC patients into distinct subgroups with different drug sensitivities, immune cell infiltrations, and responses to chemotherapy and immunotherapy. Through machine learning algorithms, three hub genes (ECH1, SLC25A28 and ULK1) were identified to be closely associated with sorafenib resistance. A novel ferroptosis-related signature comprising these genes emerged as a robust diagnostic model, validated by ROC curve analysis, for predicting sorafenib resistance in HCC patients. Furthermore, experimental validation confirmed the upregulation of ECH1, SLC25A28 and ULK1 expressions in sorafenib-resistant HCC cells, with sorafenib treatment altering their expression profiles. Knockdown of ULK1 in sorafenib-resistant HCC cells potently enhanced sorafenib-induced ferroptosis, thereby alleviating sorafenib resistance. Our findings not only identify pivotal ferroptosis-related genes as diagnostic biomarkers for sorafenib resistance but also provide insights into the role of ferroptosis in modulating sorafenib responsiveness. This study offers a promising strategy to overcome sorafenib resistance and improve patient outcomes in HCC treatment, highlighting the potential of ferroptosis-targeted therapies in cancer management.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115557"},"PeriodicalIF":4.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement component C6 deficiency exacerbates colorectal tumorigenesis by abolishing membrane attack complex formation and potentiating M2-like tumor-associated macrophage responses","authors":"Yan Hao ,&nbsp;Ling Li ,&nbsp;Xinyue Lv ,&nbsp;Luying Li ,&nbsp;Huanhuan Cui ,&nbsp;Weiguo Hu ,&nbsp;Peipei Ding","doi":"10.1016/j.intimp.2025.115576","DOIUrl":"10.1016/j.intimp.2025.115576","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, necessitating a deeper understanding of its underlying molecular mechanisms. The complement system, a prominent arsenal of innate immunity, has emerged as a pivotal regulator of tumor immunity, yet its specific role in CRC remains inadequately explored. Herein, we reported that complement C6, an indispensable component of the terminal membrane attack complex (MAC), was markedly reduced in human CRC tissues and lower levels of C6 were associated with poor overall survival (OS) in patients. In an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced murine CRC model, <em>C6</em> deficiency exacerbated colitis-associated tumorigenesis. Mechanistically, <em>C6</em> deficiency abolished MAC formation and promoted the survival of malignant transformed colorectal epithelial cells. Moreover, C6 loss also resulted in an increased presence of M2 tumor-associated macrophages (TAMs) and a significant reduction in T and B cell populations. Additionally, the absence of C6 altered the local levels of several critical chemokines and cytokines, including CCL2/MCP-1, CXCL13/BLC, CCL17/TARC, IL-11 and TGF-β1, thereby contributing to the establishment of an immunosuppressive tumor microenvironment. Collectively, our findings indicate that C6 exerts a protective role in CRC initiation by mediating MAC-dependent tumoricidal activity and modulating immune responses, highlighting its potential as a therapeutic target. Notably, pan-cancer analysis further revealed that C6 expression was consistently decreased across multiple cancer types and was strongly correlated with immune modulation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115576"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145097658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deferoxamine improves intervertebral disc degeneration by activating HIF-1α/BNIP3-mediated mitophagy and inhibiting ferroptosis","authors":"Heran Wang ,&nbsp;Zimo Zhou ,&nbsp;Tong Wu ,&nbsp;Zheng Fan ,&nbsp;Zhuoru Jin ,&nbsp;Yuxiao Cao ,&nbsp;Chenhao Huangfu ,&nbsp;Yulin Wang ,&nbsp;Xiaodong Liu ,&nbsp;Da Liu","doi":"10.1016/j.intimp.2025.115583","DOIUrl":"10.1016/j.intimp.2025.115583","url":null,"abstract":"<div><h3>Background</h3><div>Intervertebral disc degeneration (IVDD), a major cause of low back pain, is characterized by cartilage endplate (CEP) degeneration, extracellular matrix (ECM) degradation, and oxidative stress. Deferoxamine (DFO), an iron chelator, demonstrates efficacy in treating iron-overload disorders.</div></div><div><h3>Objective</h3><div>This study aimed to systematically investigate the role and molecular mechanisms of DFO in IVDD and ferroptosis.</div></div><div><h3>Methods</h3><div>We employed bioinformatics analysis, in vitro cell models, and an in vivo mouse IVDD model.</div></div><div><h3>Results</h3><div>Bioinformatics identified 65 common targets for DFO and IVDD, implicating mitochondrial function regulation, oxidative stress response, and the HIF-1α signaling pathway. In vitro, 100 μM DFO restored tert-butyl hydroperoxide (TBHP)-induced suppression of superoxide dismutase (SOD) activity, enhanced COL2 and SOX9 expression, and suppressed MMP3, COL10, and RUNX2 expression, mitigating calcification. In vivo, 100 mg/kg/day for 12 weeks DFO alleviated IVDD pathology in the IVDD model. DFO promoted mitochondrial autophagy (mitophagy) via the HIF-1α/BNIP3 axis, reduced malondialdehyde (MDA) levels, and increased glutathione (GSH) and GPX4 expression. Mechanistic studies confirmed that DFO inhibits ferroptosis and CEP degeneration by activating HIF-1α/BNIP3-mediated mitophagy.</div></div><div><h3>Conclusion</h3><div>DFO ameliorates CEP degeneration in IVDD by targeting oxidative stress, ferroptosis, and mitochondrial dysfunction. Its protective effects are mediated through multi-targeted mechanisms, prominently involving the activation of HIF-1α/BNIP3-mediated mitophagy to suppress ferroptosis. These findings highlight DFO as a promising therapeutic strategy for IVDD and ferroptosis-related pathologies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115583"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kaempferol inhibits atherosclerotic plaque development via dual-targeting of p53-p21-p16 senescence pathway and Nrf2/HO-1/NQO1 antioxidant mechanism: Insights from combined in vivo and in vitro research","authors":"Xinyi Cai ,&nbsp;Yajie Zhang ,&nbsp;Weina Zhu ,&nbsp;Ning Gu","doi":"10.1016/j.intimp.2025.115587","DOIUrl":"10.1016/j.intimp.2025.115587","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis, a leading cause of cardiovascular disease, is driven by aging-related endothelial cell senescence, oxidative stress, and inflammation. Kaempferol, a dietary flavonoid, exerts potent antioxidant and anti-senescence effects on the vasculature.</div></div><div><h3>Objective</h3><div>We investigated whether kaempferol mitigates atherosclerosis through dual suppression of vascular oxidative damage and endothelial senescence.</div></div><div><h3>Methods</h3><div>Male ApoE^−/− mice on a high-fat diet were treated with kaempferol or vehicle. Atherosclerotic lesions were quantified in the aorta (Oil Red O staining), and endothelial function was assessed by vasodilation assays. Aortic tissues were analyzed for oxidative stress markers (ROS, MDA, SOD) and inflammatory cytokines (TNF-α, IL-6). Endothelial senescence in the vasculature was evaluated by γ-H2A.X staining and expression of p53, p16^INK4a and p21. Separately, human endothelial cells were exposed to H₂O₂ to induce oxidative stress and senescence, with or without kaempferol; ROS levels and markers of cellular senescence (SA-β-gal, p53, p16^INK4a, p21) were then measured.</div></div><div><h3>Results</h3><div>Kaempferol-treated mice exhibited markedly smaller aortic plaque areas than controls. Endothelium-dependent vasorelaxation improved, and oxidative stress in the aorta was attenuated (reduced ROS/MDA, increased SOD activity). Pro-inflammatory TNF-α and IL-6 levels were suppressed, while antioxidant Nrf2 and HO-1 expression was elevated. In vitro, kaempferol significantly reduced H₂O₂-induced endothelial senescence: treated cells showed fewer SA-β-gal-positive cells and decreased expression of p16^INK4a and p21, indicating reduced cellular aging.</div></div><div><h3>Conclusion</h3><div>Kaempferol significantly ameliorates experimental atherosclerosis via simultaneous antioxidative and anti-senescent actions, highlighting its potential as a therapeutic agent for vascular disease.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115587"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMC4 promotes immune evasion by inhibiting endogenous interferon signaling and upregulating PD-L1 expression in triple negative breast cancer","authors":"Jiayu Zhu ,&nbsp;Lei Zhang ,&nbsp;Xue Hui ,&nbsp;Lingmin Shang ,&nbsp;Jianli Ma ,&nbsp;Qingyuan Zhang","doi":"10.1016/j.intimp.2025.115580","DOIUrl":"10.1016/j.intimp.2025.115580","url":null,"abstract":"<div><h3>Objective</h3><div>Triple-negative breast cancer (TNBC) is highly invasive and has an inferior prognosis, with the majority of patients deriving limited benefits from immunotherapy. Enhancing the efficacy of immune checkpoint inhibitors (ICIs) remains a formidable challenge for TNBC. Structural maintenance of chromosome 4 (SMC4), a regulator of genomic stability, has been implicated in tumor progression. However, its role in TNBC immune evasion remains unknown.</div></div><div><h3>Method</h3><div>SMC4 expression and spatial distribution in TNBC were analyzed using bioinformatics, immunohistochemistry, rt-qPCR and western blot. Immunohistochemistry was used to evaluated the association of SMC4 expression with immunotherapy response in advanced TNBC. Stable SMC4-knockdown and overexpression TNBC cell lines were established to assess tumor biology in vitro and in vivo, particularly its regulation of CD8⁺ T cell function in the tumor microenvironment (TME). Flow cytometry was used to characterize CD8⁺ T cell phenotypes. Western blot, RT-qPCR, ELISA, molecular docking and immunoprecipitation were used to evaluate the mechanism of SMC4 regulation of immune escape.</div></div><div><h3>Results</h3><div>We demonstrated that SMC4 is aberrantly overexpressed in TNBC and correlates with diminished immunotherapeutic response and unfavorable prognosis. Intriguingly, SMC4 drives tumor progression in a CD8⁺T cell-dependent manner, unveiling its non-canonical role in immune modulation. Mechanistically, SMC4 executes dual immunosuppressive functions hand, SMC4 maintains genomic stability to suppress cGAS-STING-mediated type I interferon production and CD8⁺ T cells recruitment. In contrast, SMC4 directly impaired CD8⁺T cell cytotoxicity through STING-independent PD-L1 upregulation. Knockdown SMC4 not only restored tumor immunogenicity, but also potentiated the efficacy of anti-PD-1 therapy in immunocompetent 4T1 murine models.</div></div><div><h3>Conclusion</h3><div>Our findings establish SMC4 as a dual regulator of immune evasion in TNBC and propose targeting SMC4 as a promising combinatorial strategy to overcome the current limitations in immunotherapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115580"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145097660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}