Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-09-05DOI: 10.1016/j.xcrm.2025.102335
Margaret F Schimmel, Bryan C Bourgeois, Alison K Spindt, Sage A Patel, Tiffany Chin, Gavin E Cornick, Yuqi Liu, Thomas Weimbs
{"title":"Development of a cyst-targeted therapy for polycystic kidney disease using an antagonistic dimeric IgA monoclonal antibody against cMET.","authors":"Margaret F Schimmel, Bryan C Bourgeois, Alison K Spindt, Sage A Patel, Tiffany Chin, Gavin E Cornick, Yuqi Liu, Thomas Weimbs","doi":"10.1016/j.xcrm.2025.102335","DOIUrl":"10.1016/j.xcrm.2025.102335","url":null,"abstract":"<p><p>Polycystic kidney disease (PKD) is characterized by the development of fluid-filled kidney cysts and relentless progression to renal failure. Current treatments have adverse effects and limited efficacy, enhancing the need for improved therapeutics. Here, we provide a proof of concept for the use of dimeric immunoglobulin A (IgA) (dIgA) monoclonal antibodies (mAbs) to target epithelial-enclosed cysts, by exploiting their ability to transcytose via the polymeric immunoglobulin receptor highly expressed on renal cyst-lining cells. We engineered an antagonistic dIgA mAb against the cell mesenchymal-epithelial transition (cMET) receptor, a driver of cyst progression, and demonstrated its specific binding and inhibition of cMET in vitro. In vivo studies in PKD rodent models showed efficient targeting of the mAb to renal cyst lumens and its ability to slow disease progression without apparent adverse effects. This study presents an intriguing avenue for developing antibody-based therapies for PKD and similar diseases by repurposing existing immunoglobulin G (IgG) mAbs into dIgA mAbs for superior targeting to epithelial-enclosed compartments.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102335"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008188","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}
Yong Joon Lee, Seung Hyuck Jeon, Jin Hee Yeo, Sun-Ju Byeon, Jae Hyung Jung, Heejin Nam, Minwoo Jeon, Eui-Soon Kim, Jeon Yeob Jang, Chul-Ho Kim, Kee Yang Chung, Jung Yun Lee, Shin Hwang, Jee Ye Kim, Seung-Il Kim, Jae-Ho Cheong, Chang Gon Kim, Sang Joon Shin, Su-Hyung Park, Minsun Jung, Minyong Kang, Seong Il Seo, Eui-Cheol Shin
{"title":"Tumor-specific but immunosuppressive CD39<sup>+</sup>CD8<sup>+</sup> T cells exhibit double-faceted roles in clear cell renal cell carcinoma.","authors":"Yong Joon Lee, Seung Hyuck Jeon, Jin Hee Yeo, Sun-Ju Byeon, Jae Hyung Jung, Heejin Nam, Minwoo Jeon, Eui-Soon Kim, Jeon Yeob Jang, Chul-Ho Kim, Kee Yang Chung, Jung Yun Lee, Shin Hwang, Jee Ye Kim, Seung-Il Kim, Jae-Ho Cheong, Chang Gon Kim, Sang Joon Shin, Su-Hyung Park, Minsun Jung, Minyong Kang, Seong Il Seo, Eui-Cheol Shin","doi":"10.1016/j.xcrm.2025.102360","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102360","url":null,"abstract":"<p><p>CD39<sup>+</sup>CD8<sup>+</sup> T cells are known as tumor-antigen-specific cells among CD8<sup>+</sup> tumor-infiltrating lymphocytes (TILs). However, CD39<sup>+</sup>CD8<sup>+</sup> T cells also reportedly exhibit immunosuppressive activity in hypoxic tumor models. Here, we investigate CD39<sup>+</sup>CD8<sup>+</sup> TILs in clear cell renal cell carcinoma (ccRCC), a Von Hippel-Lindau (VHL) mutation-associated hypoxic tumor. Single-cell analyses confirm that CD39<sup>+</sup>CD8<sup>+</sup> cells are a terminally exhausted subset of tumor-specific CD8<sup>+</sup> TILs. CD39<sup>+</sup>CD8<sup>+</sup> T cell development is directly induced by cAMP and T cell receptor (TCR) signaling. Analysis of a renal cell carcinoma (RCC) cohort reveals that the proportion of CD39<sup>+</sup>CD8<sup>+</sup> TILs is associated with a high tumor mutational burden and hypoxic features. Ex vivo functional assays reveal that CD39<sup>+</sup>CD8<sup>+</sup> TILs exert immunosuppressive activity via ectonucleotidase activity- and adenosine-dependent mechanisms. CD39<sup>+</sup>CD8<sup>+</sup> TIL enrichment predicts poor prognosis in patients with ccRCC yet also predicts favorable treatment responses to anti-programmed cell death protein 1 (PD-1) therapy. This paradoxical prognostic significance in ccRCC is explained by the dual properties of CD39<sup>+</sup>CD8<sup>+</sup> TILs: tumor antigen specificity and immunosuppressive activity.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102360"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079737","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":"SOX4-ZIP14-zinc metabolism mediates oncogenesis and suppresses T cell immunity in nasopharyngeal carcinoma.","authors":"Yuma Yang, Qin Liu, Jie Luo, Ziyang Qi, Shanshan Li, Lin Shen, Jishi Li, Xiaona Fang, Jiao Huang, Beilei Liu, Shan Liu, Hongyu Zhou, Lu Bai, Ching Ngar Wong, Baifeng Zhang, Danyang Zheng, Yu Zhang, Wei Dai, Lanqi Gong, Xin-Yuan Guan","doi":"10.1016/j.xcrm.2025.102300","DOIUrl":"10.1016/j.xcrm.2025.102300","url":null,"abstract":"<p><p>Subtle variations of micronutrients in the tumor microenvironment often coincide with tumor progression and immune disorders. Nevertheless, the underlying mechanisms of how micronutrients, such as metal ions, influence tumor-intrinsic properties and tumor-immune crosstalk remain inadequately characterized. Here, our integrative analysis of multi-center single-cell, spatial transcriptome sequencing, and bulk RNA sequencing (RNA-seq) cohorts reveals that nasopharyngeal carcinoma (NPC)-specific SRY-box transcription factor 4 (SOX4) governs microenvironmental and cellular zinc metabolism through its downstream target, SLC39A14 (ZIP14), a membrane zinc uptake transporter. Mechanistically, NPC cells enhance zinc uptake and activate Wnt/β-catenin signaling to initiate tumor growth, creating a zinc-deficient niche hostile to T cells. Zinc deficiency of tumor-infiltrating CD8<sup>+</sup> T cells impairs LCK phosphorylation and T cell receptor (TCR) signaling, compromising their effector function. Our study elucidates the idea that the SOX4-ZIP14-zinc metabolism axis has a multifactorial effect in NPC, fostering the malignant phenotypes of NPC and suppressing the T cell response through the deprivation of zinc metabolism.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102300"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862155","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}
Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-08-29DOI: 10.1016/j.xcrm.2025.102321
Yan-Ruide Li, Junhui Hu, Zhe Li, Enbo Zhu, Yuning Chen, Tyler Halladay, Xinyuan Shen, Ying Fang, Yichen Zhu, Zibai Lyu, Yanxin Tian, Jie Huang, Annabel S Zhao, Nathan Y Ma, Catherine Zhang, Yongpeng Xie, Hanwei Zhang, Tzung Hsiai, Arnold I Chin, Lily Wu, Lili Yang
{"title":"Multimodal targeting of metastatic renal cell carcinoma via CD70-directed allogeneic CAR-NKT cells.","authors":"Yan-Ruide Li, Junhui Hu, Zhe Li, Enbo Zhu, Yuning Chen, Tyler Halladay, Xinyuan Shen, Ying Fang, Yichen Zhu, Zibai Lyu, Yanxin Tian, Jie Huang, Annabel S Zhao, Nathan Y Ma, Catherine Zhang, Yongpeng Xie, Hanwei Zhang, Tzung Hsiai, Arnold I Chin, Lily Wu, Lili Yang","doi":"10.1016/j.xcrm.2025.102321","DOIUrl":"10.1016/j.xcrm.2025.102321","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) represents about 90% of kidney cancers, with 30%-40% of patients developing metastatic disease despite current treatments. Conventional chimeric antigen receptor (CAR)-T therapy targeting CD70 shows promise but faces challenges due to its autologous, personalized nature. Here, we develop allogeneic CD70-directed CAR-engineered invariant natural killer T (<sup>Allo</sup>CAR70-NKT) cells from hematopoietic stem and progenitor cells using a clinically guided culture method. These cells expand robustly with high purity and no fratricide risk. <sup>Allo</sup>CAR70-NKT cells exhibit potent cytotoxicity against primary and metastatic RCC via CAR- and natural killer (NK) receptor-mediated mechanisms and selectively target the immunosuppressive tumor microenvironment (TME) through T cell receptor (TCR) recognition. Additionally, they eliminate CD70<sup>+</sup> host alloreactive T cells, promoting therapeutic persistence. Taken together, our findings support the therapeutic potential of <sup>Allo</sup>CAR70-NKT cells as a next-generation, off-the-shelf immunotherapy with dual tumor- and TME-targeting functionality and the added capacity to eliminate alloreactive T cells, which offers a compelling strategy for treating metastatic RCC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102321"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944701","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}
Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-08-22DOI: 10.1016/j.xcrm.2025.102295
Jacob S Bedia, Antonio Delgado-Gonzalez, Ying-Wen Huang, Veronica D Gonzalez, Ionut-Gabriel Funingana, Zainab Rahil, Alyssa Mike, Alexis Lowber, Maria Vias, Alan Ashworth, James D Brenton, Wendy J Fantl
{"title":"Coordinated protein modules define DNA damage responses to carboplatin at single-cell resolution in human ovarian carcinoma models.","authors":"Jacob S Bedia, Antonio Delgado-Gonzalez, Ying-Wen Huang, Veronica D Gonzalez, Ionut-Gabriel Funingana, Zainab Rahil, Alyssa Mike, Alexis Lowber, Maria Vias, Alan Ashworth, James D Brenton, Wendy J Fantl","doi":"10.1016/j.xcrm.2025.102295","DOIUrl":"10.1016/j.xcrm.2025.102295","url":null,"abstract":"<p><p>Tubo-ovarian high-grade serous carcinoma (HGSC), the most lethal gynecologic malignancy, initially responds to platinum-based chemotherapy, but due to frequent defects in the DNA damage response (DDR), most tumors develop resistance. The molecular mechanisms underlying clinical platinum resistance remain poorly defined with no biomarkers or targeted therapies to improve outcomes. Here, applying mass cytometry, we quantify phosphorylation and abundance of DDR proteins in carboplatin-treated HGSC cell line models. Despite similar levels of intranuclear platinum, a proxy for carboplatin uptake, cells follow divergent fates, reflecting DDR heterogeneity. Unsupervised analysis reveals a continuum of DDR states, and matrix factorization identifies eight protein modules. The activity of one module, containing canonical DDR proteins, increases in carboplatin-sensitive cells. Resistant cells engage a broader DDR protein module. These findings demonstrate the ability of single-cell proteomics to identify functional DDR states and reveal a DDR sensitivity module as a promising biomarker for clinical stratification and therapeutic decisions in HGSC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102295"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944708","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}
Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-08-25DOI: 10.1016/j.xcrm.2025.102313
Ksenija Slavic Obradovic, Florian Ebner, Artem V Artemov, Martina Miotto, Paula-Elena Traexler, Robin Jacob, Ha Pham Thi Thanh, Regina Ruzicka, Andreas Wernitznig, Ines Baumann, Daniel Gerlach, Maria-Antonietta Impagnatiello, Salvatore Siena, Mary Murphy, Reniqua House, Ulrich Reiser, Valeria Santoro, Johannes Popow, Sebastian Carotta, Anke Baum, Jesse Lipp, Alberto Bardelli, Ulrike Tontsch-Grunt, Mariangela Russo, Martin Aichinger
{"title":"Combining BET inhibition with SMAC mimetics restricts tumor growth and triggers immune surveillance in preclinical cancer models.","authors":"Ksenija Slavic Obradovic, Florian Ebner, Artem V Artemov, Martina Miotto, Paula-Elena Traexler, Robin Jacob, Ha Pham Thi Thanh, Regina Ruzicka, Andreas Wernitznig, Ines Baumann, Daniel Gerlach, Maria-Antonietta Impagnatiello, Salvatore Siena, Mary Murphy, Reniqua House, Ulrich Reiser, Valeria Santoro, Johannes Popow, Sebastian Carotta, Anke Baum, Jesse Lipp, Alberto Bardelli, Ulrike Tontsch-Grunt, Mariangela Russo, Martin Aichinger","doi":"10.1016/j.xcrm.2025.102313","DOIUrl":"10.1016/j.xcrm.2025.102313","url":null,"abstract":"<p><p>Second mitochondrial activator of caspase (SMAC) mimetics (SMACm) and bromodomain and extra-terminal domain (BET) inhibitors (BETi) are two distinct classes of novel anticancer therapeutics. So far, broad clinical benefit for either monotherapy has not been achieved, calling for effective combination strategies. We show that the combination of BI 891065, a monovalent oral SMACm antagonist of inhibitor of apoptosis protein 1 (cellular inhibitor of apoptosis protein 1 [cIAP1]), and BI 894999, a potent and selective oral BETi, significantly impaired cancer cell proliferation irrespective of tissue context. Interestingly, we observed various forms of cell death pointing at distinct, but functionally converging, modulation of cell death-promoting pathways. A multi-omic analysis using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and advanced flow cytometry of a syngeneic model of pancreatic ductal adenocarcinoma (PDAC) unveils distinct phenotypic correlations of augmented anti-tumor immunity and a substantially reduced immunosuppressive tumor microenvironment (TME). Collectively, this study presents BETi and SMACm as a promising drug combination for patients with cancer with a multi-layered impact on both tumor cell-intrinsic and TME-dependent mechanisms.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102313"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944746","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}
Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-08-25DOI: 10.1016/j.xcrm.2025.102309
Xiaojing Jia, Chunyan Hu, Yu Xu, Yue Yin, Hong Lin, Ruizhi Zheng, Mian Li, Min Xu, Tiange Wang, Zhiyun Zhao, Hong Qiao, Guijun Qin, Yingfen Qin, Xulei Tang, Zhen Ye, Ruying Hu, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Qin Wan, Gang Chen, Zhengnan Gao, Guixia Wang, Feixia Shen, Xuejiang Gu, Zuojie Luo, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Yinfei Zhang, Tianshu Zeng, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Donghui Li, Shenghan Lai, Lulu Chen, Jiajun Zhao, Yiming Mu, Guang Ning, Yuhong Chen, Jieli Lu, Yufang Bi, Weiqing Wang
{"title":"Revisiting obesity thresholds for cardiovascular disease and mortality risk in Chinese adults: Age- and gender-specific insights.","authors":"Xiaojing Jia, Chunyan Hu, Yu Xu, Yue Yin, Hong Lin, Ruizhi Zheng, Mian Li, Min Xu, Tiange Wang, Zhiyun Zhao, Hong Qiao, Guijun Qin, Yingfen Qin, Xulei Tang, Zhen Ye, Ruying Hu, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Qin Wan, Gang Chen, Zhengnan Gao, Guixia Wang, Feixia Shen, Xuejiang Gu, Zuojie Luo, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Yinfei Zhang, Tianshu Zeng, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Donghui Li, Shenghan Lai, Lulu Chen, Jiajun Zhao, Yiming Mu, Guang Ning, Yuhong Chen, Jieli Lu, Yufang Bi, Weiqing Wang","doi":"10.1016/j.xcrm.2025.102309","DOIUrl":"10.1016/j.xcrm.2025.102309","url":null,"abstract":"<p><p>Current obesity classifications may not adequately reflect age- and gender-specific risks in diverse populations. In a prospective cohort study of 166,285 Chinese adults aged ≥40 years without prior cardiovascular disease (CVD) or cancer, we evaluate optimal thresholds of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) for predicting incident CVD and all-cause mortality. We observe monotonically increasing dose-response associations of BMI, WC, and WHR with CVD risk but U-shaped relationships with all-cause mortality. The optimal obesity thresholds based on all-cause mortality risk differ by gender, with the lowest mortality risks occurring at BMI 26.3 kg/m<sup>2</sup>, WC 88 cm, and WHR 0.90 in men and BMI 25.4 kg/m<sup>2</sup>, WC 83 cm, and WHR 0.85 in women. Moreover, higher adiposity appears protective in older adults. These findings highlight the need for population-specific obesity criteria to enhance clinical risk assessment and public health strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102309"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944832","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}
{"title":"The cardiometabolic paradox in women.","authors":"Amanda R Jowell, Emily S Lau, Susan Cheng","doi":"10.1016/j.xcrm.2025.102294","DOIUrl":"10.1016/j.xcrm.2025.102294","url":null,"abstract":"<p><p>The prevalence of many metabolic disease traits is greater in men, but their associated relative risk for cardiovascular disease outcomes is greater in women. This paradox contributes to under-recognition of the excess metabolic-associated cardiovascular risks seen in women.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 9","pages":"102294"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079669","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}
{"title":"Targeting AQP5-mediated arginine deprivation in gastric cancer stem cells restores NK cell anti-tumor immunity.","authors":"Rou Zhao, Baoyu He, Lunhua Huang, Yanli Wu, Ting Liu, Jilan Liu, Mingsheng Zhao, Tao Zhong, Yanhua Zhang, Xiao Zhang, Huabao Xiong, Bin Zhang, Qingli Bie","doi":"10.1016/j.xcrm.2025.102333","DOIUrl":"10.1016/j.xcrm.2025.102333","url":null,"abstract":"<p><p>Natural killer (NK) cells exhibit impaired anti-tumor activity upon entering the tumor microenvironment (TME); however, the precise mechanism(s) remains elusive. In this study, we demonstrate that AQP5<sup>+</sup> gastric cancer stem cells contribute to the dysfunction of NK cells by reprogramming the urea cycle (UC). Mechanistically, AQP5 competitively binds ATP-dependent RNA helicase A (DHX9) over karyopherin subunit beta 1 (KPNB1), inhibiting DHX9 nuclear translocation and transcriptionally down-regulating argininosuccinate synthase 1 (ASS1). Low-arginine condition in the TME reshaped by AQP5<sup>+</sup> tumor cells weakens NK cell function by limiting NO synthesis. Notably, preclinical murine models confirm that oral arginine supplements improve the NK cell-directed killing against organoids generated by AQP5<sup>High</sup> GC (gastric cancer) tissues. Besides, AQP5<sup>+</sup> tumor cells also redirect the UC to the TCA cycle, which stores the saved nitrogen in glutamine by promoting glutamate-ammonia ligase (GLUL) stability. This study uncovers the evidence of AQP5<sup>+</sup> cancer stem cells impairing NK cell cytotoxicity by changing self-metabolism patterns.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 9","pages":"102333"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079723","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}
{"title":"Berberine for preventing colorectal adenoma recurrence and neoplasm occurrence: 6-Year follow-up of a randomized clinical trial.","authors":"Yong-Jie Tan, Tian-Hui Zou, Ke Yu, Jian-Qiu Sheng, Peng Jin, Ming-Jie Zhang, Xiao-Ping Zou, Xiao-Tan Dou, Si-De Liu, Shao-Hui Huang, Jian-Lin Ren, Xiao-Ning Yang, Zhan-Ju Liu, Xiao-Min Sun, Bang-Mao Wang, Hai-Long Cao, Ya-Xuan Zhang, Qin-Yan Gao, Hui-Min Chen, Yun Cui, Ying-Xuan Chen, Jing-Yuan Fang","doi":"10.1016/j.xcrm.2025.102293","DOIUrl":"10.1016/j.xcrm.2025.102293","url":null,"abstract":"<p><p>Berberine has been reported as a safe and effective pharmacological agent to reduce colorectal adenoma recurrence after polypectomy. This retrospective cohort study is an extended follow-up of a previous clinical trial (NCT02226185) during the post-treatment observational phase. We aim to evaluate the long-term protective effects of berberine on adenoma recurrence. Among 895 patients who finished the previous 2-year randomized trial, we recruited 781 patients at 7 clinical centers across 6 provinces in China. The primary outcome is adenoma recurrence. Between December 29, 2018, and October 10, 2024, 648 patients underwent at least one colonoscopy during the follow-up. The protective effects of berberine persist for at least 6 years after treatment cessation, with lower adenoma recurrence rate (34.7% vs. 52.1%) and lower neoplasm occurrence rate (63.4% vs. 71.0%). Berberine may serve as a potential long-term preventive agent against adenoma recurrence after polypectomy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102293"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834255","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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