{"title":"Targeting oncogenic SOX2 condensates suppresses squamous cell carcinoma progression.","authors":"Siyuan Luan, Jun Sun, Yijun Dong, Jin Tan, Xin Xiao, Jintong Zhang, Xiaokun Li, Jianfeng Zhou, Pinhao Fang, Haowen Zhang, Shangwei Sun, Zewen Wang, Jian Wang, Tara Sr Chen, Xiaoting Chen, Yushang Yang, Haopeng Yu, Hui Yang, Longqi Chen, Xiaoxi Zeng, An-Yuan Guo, Junjun Ding, Yong Yuan","doi":"10.1016/j.xcrm.2026.103117","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103117","url":null,"abstract":"<p><p>Squamous cell carcinomas (SCCs) comprise a group of lethal malignancies, yet developing SCC-specific therapies remains challenging, largely due to a lack of druggable targets. We identify SOX2 condensation as a shared cancer hallmark across esophageal, head and neck, and lung SCCs. Within SOX2, the activation domain 1 (AD1) acts as the condensate-promoting region via its aromatic and hydrophobic residues. Site-specific mutagenesis, orthotopic mouse models, and multi-omics sequencing demonstrate that SOX2 condensates upregulate oncogene expression by enhancing SOX2 chromatin occupancy, H3K27ac enrichment, and chromatin interactions at oncogenic loci such as FGFR2, thereby promoting SCC progression. An FDA-approved drug screen reveals that the proteasome inhibitor ixazomib disrupts SOX2 condensates in an HSP70-dependent manner. Upon ixazomib treatment, the substrate-binding domain of HSP70 blocks SOX2 AD1, selectively dissolving SOX2 condensates, downregulating oncogene expression, and suppressing condensate-positive SCC patient-derived xenografts. These findings highlight targeting SOX2 condensates with proteasome inhibitors as an SCC-specific, biomarker-guided therapeutic strategy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103117"},"PeriodicalIF":14.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Isobavachalcone targets deubiquitinase OTUB1 to induce PD-L1 degradation and enhances antitumor immunity.","authors":"Qing Zhang, Simeng Li, Mengting Xu, Hanchi Xu, Haiyang Zhou, Hongmei Hu, Dianping Yu, Linyang Li, Xiaoyu Tao, Xuwen Lin, Xinru Li, Shize Xie, Xinying Xue, Qun Wang, Tao Yang, Weidong Zhang, Sanhong Liu","doi":"10.1016/j.xcrm.2026.103113","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103113","url":null,"abstract":"<p><p>PD-L1-mediated immunosuppression is a key mechanism underlying tumor immune evasion, whereas PD-1/PD-L1 blockade therapies remain limited by low response rates and acquired resistance. Through small-molecule screening, we identify isobavachalcone (IBC), a naturally derived compound that modulates PD-L1 homeostasis by targeting the deubiquitinase OTUB1. Mechanistically, IBC targets OTUB1 at the His217 residue and suppresses its deubiquitinase activity, thereby promoting K48-linked polyubiquitination of PD-L1 and its proteasome-dependent degradation. Functionally, IBC reduces tumor cell PD-L1 expression and enhances CD8<sup>+</sup> T cell-mediated cytotoxicity. In PD-L1-deficient tumor models, IBC fails to further enhance antitumor activity, indicating that PD-L1 is required for IBC-mediated immune regulation. Moreover, IBC combined with anti-CTLA-4 therapy further enhanced antitumor efficacy. Together, these findings highlight IBC as a potential drug candidate that promotes PD-L1 degradation and demonstrate the therapeutic potential of targeting the OTUB1-PD-L1 axis to improve immune checkpoint therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103113"},"PeriodicalIF":14.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting MMGT1 enhances immunotherapy efficacy in triple-negative breast cancer.","authors":"Shaoqing Liu, Hongbing Liu, Mengying Zhang, Kaiyuan Guo, Shilin Tong, Nuo Jiang, Jinxue Zhou, Linlin Yan, Mien-Chie Hung, Chenhao Zhou, Yanzhao Zhou, Min Xu","doi":"10.1016/j.xcrm.2026.103120","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103120","url":null,"abstract":"<p><p>The role of senescent tumor cells in modulating the immune microenvironment and influencing immunotherapy efficacy remains poorly understood. In this study, we investigate the function of the senescence-associated gene membrane magnesium transporter 1 (MMGT1) in triple-negative breast cancer (TNBC) immunotherapy. MMGT1 is upregulated in TNBC and correlates with poor prognosis. Mammary gland-specific knockout of Mmgt1 significantly impedes tumor growth. Mechanistically, MMGT1 promotes lipid metabolism by facilitating translocation of the SCAP-SREBP1 complex to the Golgi apparatus, thereby suppressing cellular senescence. Notably, senescent TNBC cells enhance CD8<sup>+</sup> T cell proliferation and cytotoxicity through CCL20 secretion. Furthermore, a positive feedback loop exists between MMGT1 and SREBP1. In vivo, AZ191 downregulates MMGT1 expression, which suppresses tumor growth and enhances the efficacy of anti-PD-1 therapy. Collectively, these findings reveal a critical role for MMGT1 in shaping the TNBC immune microenvironment and suggest that targeting MMGT1 represents a promising strategy to improve anti-PD-1 immunotherapy outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103120"},"PeriodicalIF":14.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiajia Li, Lu Han, Qi Zhu, Nan Liu, Hongyu Ma, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han
{"title":"NKG2D overexpression potentiates CAR-T cells through costimulation by tumor NKG2D ligands.","authors":"Jiajia Li, Lu Han, Qi Zhu, Nan Liu, Hongyu Ma, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han","doi":"10.1016/j.xcrm.2026.103116","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103116","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, but durable efficacy remains limited by insufficient CAR-T cell persistence. Here, we show that activated CAR-T cells upregulate multiple NKG2D ligands (NKG2DLs), increasing their susceptibility to natural killer (NK) cell-mediated CAR-T cell cytotoxicity. To address this vulnerability, we engineer CAR-T cells to overexpress full-length NKG2D (CAR-NG). NKG2D overexpression reduces the surface accessibility of endogenous NKG2DLs without decreasing their total protein abundance. In parallel, engagement of tumor-expressed NKG2DLs in trans provides additional costimulatory signals, enhancing CAR-T cell activation and proliferation while attenuating exhaustion-associated phenotypes. In hematologic and solid tumor models, CAR-NG cells exhibit reduced susceptibility to NK-cell-mediated cytotoxicity, improved tumor control, increased in vivo expansion, deeper tumor infiltration, and no evident additional toxicity compared with conventional CAR-T cells. These findings identify NKG2D overexpression as an engineering strategy that enhances CAR-T antitumor activity primarily through tumor NKG2DL-dependent trans costimulation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103116"},"PeriodicalIF":14.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Safety and efficacy of high-current tTIS targeting left sgACC for major depressive disorder: A randomized, double-blind, sham-controlled trial.","authors":"Mengmeng Wang, Wei Wu, Quanming Zheng, Hao Zhou, Jiecheng Ren, Huixing Gou, Xue'er Meng, Guanbao Cui, Jingjing Sun, Jiahui Zhou, Xiyun Chen, Jian Guo, Shikang Li, Zhen He, Dexue Ge, Gang Wang, Qiuyu Yuan, Dongliang Jiao, Xinming Yu, Bin Wang, Mingsong Zhang, Chuangchuang Chang, Ginger Qinghong Zeng, Xiaochu Zhang","doi":"10.1016/j.xcrm.2026.103112","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103112","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a leading cause of disability, and non-invasive stimulation of deep brain circuits such as the subgenual anterior cingulate cortex (sgACC) remains challenging. This randomized, double-blind, sham-controlled trial recruits 96 adults with moderate-to-severe MDD who received 10 sessions of 2 mA low-current, 15 mA high-current, or sham transcranial temporal interference stimulation (tTIS) targeting the left sgACC. The high-current group shows significantly greater reductions in depressive symptoms (17-item Hamilton Depression Rating Scale [HDRS-17] score) post-treatment and at 1-month follow-up compared with sham and outperforms the low-current group post-treatment. Exploratory Pittsburgh Sleep Quality Index (PSQI) analyses suggest improved sleep quality in both active groups, whereas anxiety outcomes show no intergroup differences. High-current tTIS is safe and well tolerated, with only transient tingling. These findings provide preliminary evidence that sgACC-targeted tTIS relieves depressive symptoms safely, with more robust short-to medium-term effects observed under the 15 mA protocol. This trial registers on Chictr.org.cn (ChiCTR2400094971).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103112"},"PeriodicalIF":14.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Braun, Nicholas Dana, Hilary R Hernan, Shalini Sahni, Christina M Scribano, Christin Johnson, Lindsey Vedder, Erika von Euw, Julie Zweng, Ellen Wargowski, Aishwarya Sunil, Deepa Sharma, Josh Routh, Katherine Rexroad, Amreen Nasreen, Payton McDonnell, Victor Jergens, Catarina Costa, Richard Zuniga, Giuseppe V Toia, Paras M Patel, Stephanie McGregor, Robert C G Martin, Umair Majeed, Debabrata Mukhopadhyay, Yanyan Lou, Nima Kokabi, James W Jakub, David Hays, Andrew K Godwin, Victoria Giffi, Alexander Gelbard, Andreas Friedl, Emma Kate Duimstra, Roxana S Dronca, Ruqin Chen, Heather Chalfin, Santanu Bhattacharya, Barbara Broome, Hani M Babiker, Tarun Chandra, Sean Caenepeel, Laura C F Hrycyniak, Chetan Sood, Hilario Ramos, Premal Patel, Pooja Advani, Hinco J Gierman, Janis Taube
{"title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies.","authors":"David Braun, Nicholas Dana, Hilary R Hernan, Shalini Sahni, Christina M Scribano, Christin Johnson, Lindsey Vedder, Erika von Euw, Julie Zweng, Ellen Wargowski, Aishwarya Sunil, Deepa Sharma, Josh Routh, Katherine Rexroad, Amreen Nasreen, Payton McDonnell, Victor Jergens, Catarina Costa, Richard Zuniga, Giuseppe V Toia, Paras M Patel, Stephanie McGregor, Robert C G Martin, Umair Majeed, Debabrata Mukhopadhyay, Yanyan Lou, Nima Kokabi, James W Jakub, David Hays, Andrew K Godwin, Victoria Giffi, Alexander Gelbard, Andreas Friedl, Emma Kate Duimstra, Roxana S Dronca, Ruqin Chen, Heather Chalfin, Santanu Bhattacharya, Barbara Broome, Hani M Babiker, Tarun Chandra, Sean Caenepeel, Laura C F Hrycyniak, Chetan Sood, Hilario Ramos, Premal Patel, Pooja Advani, Hinco J Gierman, Janis Taube","doi":"10.1016/j.xcrm.2026.103114","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103114","url":null,"abstract":"<p><p>Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy across prospective, multicenter observational studies. Hierarchical clustering of changes in cytokine production between an IgG baseline phase and an ICI treatment phase identified two clusters: heatmap responder and nonresponder. A binary classifier (elive index) using eight cytokines achieved an area under the curve (AUC) of 0.99 for heatmap cluster prediction. elive index aligned with clinical benefit in 93% (26/28) of patients (p = 3.2 × 10<sup>-5</sup>) and identified 83% (10/12) of objective responders. elive responders were found among biomarker-negative patients, highlighting the platform as a scalable approach that may complement existing companion diagnostics. This study was registered at ClinicalTrials.gov (NCT05478538, NCT05520099, NCT06349642, and NCT07327489).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103114"},"PeriodicalIF":14.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lexuan Wang, Yang Chen, Yanyu Shang, Jia Liu, Muyuan Zhao, Lei Jin, Yichenxi Shi, Ruili Zhang, Zhuang Chen, Ting Yin, Chaoqiang Qiao, Zhongliang Wang
{"title":"Orally delivered metabolically reprogrammed probiotics for cascade-activated antitumor immunity in colorectal cancer.","authors":"Lexuan Wang, Yang Chen, Yanyu Shang, Jia Liu, Muyuan Zhao, Lei Jin, Yichenxi Shi, Ruili Zhang, Zhuang Chen, Ting Yin, Chaoqiang Qiao, Zhongliang Wang","doi":"10.1016/j.xcrm.2026.103111","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103111","url":null,"abstract":"<p><p>Immunotherapy for colorectal cancer (CRC) remains limited due to the inherently low tumor immunogenicity and the profoundly immunosuppressive tumor microenvironment (TME). Herein, capitalizing on the metabolic traits and anatomical accessibility of CRC, we propose a broadly applicable oral strategy based on metabolically engineered bacteria (EcN-HlpA-CGL [EHC]) for CRC immunotherapy. Mechanistically, cystathionine γ-lyase expressed by EHC disrupts redox homeostasis, triggering ferroptosis in CRC cells and thereby enhancing tumor immunogenicity. Concurrently, the intrinsic adjuvant activity of the bacteria amplifies the cancer-immunity cycle driven by immunogenic cell death and remodels the immunosuppressive TME. In vivo studies demonstrate that this orally delivered engineered bacterial platform not only suppresses the growth of orthotopic CRC tumors but also inhibits metastatic progression, indicating the induction of a potent systemic immune response. Immune profiling confirms robust systemic and gut mucosal immune activation following oral administration. Collectively, this oral metabolically engineered bacterial platform is precisely tailored to the features of CRC and offers a safe and effective immunotherapeutic strategy for this malignancy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103111"},"PeriodicalIF":14.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prognostic value of cfDNA methylation in locally advanced esophageal squamous cell cancer treated with neoadjuvant immunochemoradiotherapy.","authors":"Baoqing Chen, Zimeng Li, Yin Li, Xingyuan Cheng, Wendi Xuzhang, Ruixi Wang, Yilu Gao, Peiying Cen, Chen Yi, Lirong Tian, Guangkuo Wei, Zhengyang Li, Bingzhong Jing, Shuchun Wang, Qiaoqiao Li, Hong Yang, Huiyan Luo, Mian Xi","doi":"10.1016/j.xcrm.2026.103102","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103102","url":null,"abstract":"<p><p>We prospectively evaluated whether longitudinal cfDNA methylation predicts pathological complete response (pCR) and survival in 70 patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunochemoradiotherapy. Serial plasma samples (n = 183) were collected at four time points: pre-neoadjuvant treatment (NAT), post-NAT, pre-surgery, and post-surgery. Targeted whole-genome cfDNA methylation sequencing was performed, and cancer detection (CD) values were calculated with positivity, defined as CD ≥ 0.7. CD positivity dropped from 74% pre-NAT to 31% post-NAT (p < 0.001). Pre-surgery CD positivity was significantly higher in non-pCR versus pCR patients (33% vs. 0%; p = 0.028). A model incorporating post-NAT CD value and clinical factors achieved an area under the curve (AUC) of 0.764 for pCR. Post-NAT CD-negative patients had significantly improved disease-free survival (DFS; hazard ratio [HR] = 0.33; p = 0.035). Findings were reproduced in an expanded 30-patient cohort. Dynamic cfDNA methylation monitoring is associated with pCR and DFS, warranting further validation in larger cohorts.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103102"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lei Zhao, Shan An, Mengqian Gao, Cui Shen, Meng Li, Yangjing Li, Ning Liu, Jin Chen, Wenjun Wan, Lichen Yin, Yiran Zheng
{"title":"Lipid-engineered antibody-based therapeutics target inflamed joints and lymph nodes to enhance rheumatoid arthritis treatment.","authors":"Lei Zhao, Shan An, Mengqian Gao, Cui Shen, Meng Li, Yangjing Li, Ning Liu, Jin Chen, Wenjun Wan, Lichen Yin, Yiran Zheng","doi":"10.1016/j.xcrm.2026.103094","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103094","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint damage. Although antibody (Ab)-based biologic disease-modifying anti-rheumatic drugs (bDMARDs) have transformed RA treatment, their efficacy remains limited in many patients. Here, we conjugate Ab-based bDMARDs with pegylated diacyllipid (DP) motifs to enable their albumin hitchhiking after subcutaneous administration, thereby targeting these lipid-drug conjugates (LDCs) to both inflamed joints and lymph nodes (LNs) for enhanced and concurrent immunosuppression. Multivalent DP conjugation allows bDMARDs larger than albumin to engage multiple albumin molecules, further enhancing albumin-mediated targeting. In a collagen-induced arthritis model, DP modification substantially improves the therapeutic efficacy of two representative bDMARDs, TNF-α-neutralizing Ab (aTNF-α) and CTLA4-immunoglobin recombinant protein (CTLA4), without detectable additional safety risks. bDMARDs bearing two DP moieties significantly outperform their single-DP-modified counterparts, consistent with more extensive albumin engagement. LDC offers a potent, facile, and broadly applicable strategy for targeting Ab-based therapeutics to inflamed tissues and LNs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103094"},"PeriodicalIF":14.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-08-28DOI: 10.1016/j.xcrm.2026.103009
Bohan Zhang, Yifan Zhang, Yi Cai, Siyuan Cheng, Zihan Han, Xiaochen Yin, Tong Xie, Yan Tan, Yang Feng, Yuxin Wang, Xiaohuan Guo, Lin Shen, Zhi Peng
{"title":"Lactobacillus salivarius potentiates gastrointestinal cancer immunotherapy through its metabolite chenodeoxycholic acid.","authors":"Bohan Zhang, Yifan Zhang, Yi Cai, Siyuan Cheng, Zihan Han, Xiaochen Yin, Tong Xie, Yan Tan, Yang Feng, Yuxin Wang, Xiaohuan Guo, Lin Shen, Zhi Peng","doi":"10.1016/j.xcrm.2026.103009","DOIUrl":"10.1016/j.xcrm.2026.103009","url":null,"abstract":"<p><p>Immune checkpoint inhibitor therapy has improved gastrointestinal (GI) cancer management; however, many patients exhibit resistance. Although gut microbiota influences immunotherapeutic responses, the underlying mechanisms remain unclear. Metagenomic analysis of 278 GI cancer patients reveals that Lactobacillus salivarius (L. salivarius) is enriched in responders and enhances anti-PD-1 efficacy in syngeneic tumor models by increasing the infiltration of antitumor M1-like macrophages and CD8<sup>+</sup> T cells and enhancing CD8<sup>+</sup> T cell effector function. L. salivarius-associated chenodeoxycholic acid (CDCA) is identified as a functional metabolite. CDCA recapitulates the antitumor effects of L. salivarius and significantly improves anti-PD-1 efficacy in vivo, an effect attenuated by depleting macrophages or CD8<sup>+</sup> T cells. Mechanistically, CDCA-induced reactive oxygen species triggers immunogenic cell death in tumor cells and polarizes macrophages toward antitumor M1 phenotype, activating CD8<sup>+</sup> T cell antitumor immunity. These findings identify L. salivarius and its associated metabolite CDCA as a promising adjuvant for potentiating immunotherapy in GI cancers.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103009"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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