Lysosomes are essential for cellular homeostasis, serving as degradative organelles that recycle nutrients. Whether and how lysosomes maintain membrane integrity under energy stress is poorly understood. Here, we found that the uptake of lipid droplets by lysosomes during glucose starvation provokes disruption of lysosomal membranes. We identified tectonin beta-propeller repeat-containing protein 1 (TECPR1) as a critical mediator of lysosomal repair during glucose starvation or LLOMe-induced lysosomal membrane permeabilization. TECPR1 is recruited to damaged lysosomes via interaction with PI4P on damaged lysosomal membranes. It interacts with KIF1A to facilitate tubule formation from damaged lysosomes, enabling the removal of damaged membrane components and promoting lysosomal repair. Our in vitro reconstituted tubulation process provided further evidence that TECPR1 coordinates with KIF1A to drive tubulation from PI4P-enriched giant unilamellar vesicles. TECPR1-mediated lysosomal repair is essential for maintaining lipid metabolism and cellular survival during an energy crisis, as TECPR1 deficiency exacerbates starvation-induced liver damage in a high-fat diet-induced MAFLD mouse model. Our findings demonstrate a previously unrecognized role of TECPR1 in lysosomal repair, revealing its critical contributions to energy stress adaptation and liver protection. This work provides new insight into mechanisms of lysosomal repair and their implications for metabolic and lysosome-related disorders.
{"title":"Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis","authors":"Hanmo Chen, Chaojun Zhang, Yuhui Fu, Linsen Li, Xiaoyu Qiao, Shen Zhang, Hanyan Luo, She Chen, Xiaoxia Liu, Qing Zhong","doi":"10.1038/s41422-025-01193-6","DOIUrl":"10.1038/s41422-025-01193-6","url":null,"abstract":"Lysosomes are essential for cellular homeostasis, serving as degradative organelles that recycle nutrients. Whether and how lysosomes maintain membrane integrity under energy stress is poorly understood. Here, we found that the uptake of lipid droplets by lysosomes during glucose starvation provokes disruption of lysosomal membranes. We identified tectonin beta-propeller repeat-containing protein 1 (TECPR1) as a critical mediator of lysosomal repair during glucose starvation or LLOMe-induced lysosomal membrane permeabilization. TECPR1 is recruited to damaged lysosomes via interaction with PI4P on damaged lysosomal membranes. It interacts with KIF1A to facilitate tubule formation from damaged lysosomes, enabling the removal of damaged membrane components and promoting lysosomal repair. Our in vitro reconstituted tubulation process provided further evidence that TECPR1 coordinates with KIF1A to drive tubulation from PI4P-enriched giant unilamellar vesicles. TECPR1-mediated lysosomal repair is essential for maintaining lipid metabolism and cellular survival during an energy crisis, as TECPR1 deficiency exacerbates starvation-induced liver damage in a high-fat diet-induced MAFLD mouse model. Our findings demonstrate a previously unrecognized role of TECPR1 in lysosomal repair, revealing its critical contributions to energy stress adaptation and liver protection. This work provides new insight into mechanisms of lysosomal repair and their implications for metabolic and lysosome-related disorders.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 1","pages":"51-71"},"PeriodicalIF":25.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1038/s41422-025-01200-w
Fangqiu Fu, Jun Shang, Yueren Yan, He Jiang, Han Han, Hui Yuan, Zhendong Gao, Jingcheng Yang, Jian Gao, Jun Wang, Yunjian Pan, Yicong Lin, Ting Ye, Yiliang Zhang, Yawei Zhang, Jiaqing Xiang, Hong Hu, Zhiwei Cao, Yuanting Zheng, Yuan Li, Yang Zhang, Li Jin, Leming Shi, Haiquan Chen
Lung adenocarcinoma (LUAD) progresses from pre-invasive to invasive stages, as well as from ground-glass opacities (GGOs) to solid nodules. However, the dynamic genomic and transcriptomic changes underlying LUAD progression are incompletely understood. Here, we performed whole-genome and transcriptome sequencing on 1008 LUAD samples from 954 patients who underwent surgery at Fudan University Shanghai Cancer Center, with comprehensive follow-up data. There was one atypical adenomatous hyperplasia, 42 adenocarcinomas in situ, 116 minimally invasive adenocarcinomas, and 849 invasive adenocarcinomas spanning all pathological stages. EGFR was the most frequently mutated gene in the study cohort, followed by TP53, RBM10, KRAS, and KMT2D. Mutation frequencies of tumor suppressor genes, such as TP53, RB1, MGA, KEAP1, and STK11, increased as the disease progressed to higher stages. A higher level of genomic instability was seen in LUAD compared with AAH/AIS/MIA samples, characterized by a higher tumor mutation burden, increased somatic copy number alteration burden, and increased structural variation burden. Notably, MAP2K1 E102–I103 deletion was frequently observed in pre-invasive samples, which endowed alveolar type II cells with increased growth potential and initiated tumor formation, suggesting that it is a potential driver mutation of LUAD. In summary, our study highlights key molecular changes during the stepwise progression of LUAD, provides insights into the identification of novel therapeutic targets, and helps to define the curative time window for this disease.
{"title":"Genomic and transcriptomic dynamics in the stepwise progression of lung adenocarcinoma","authors":"Fangqiu Fu, Jun Shang, Yueren Yan, He Jiang, Han Han, Hui Yuan, Zhendong Gao, Jingcheng Yang, Jian Gao, Jun Wang, Yunjian Pan, Yicong Lin, Ting Ye, Yiliang Zhang, Yawei Zhang, Jiaqing Xiang, Hong Hu, Zhiwei Cao, Yuanting Zheng, Yuan Li, Yang Zhang, Li Jin, Leming Shi, Haiquan Chen","doi":"10.1038/s41422-025-01200-w","DOIUrl":"10.1038/s41422-025-01200-w","url":null,"abstract":"Lung adenocarcinoma (LUAD) progresses from pre-invasive to invasive stages, as well as from ground-glass opacities (GGOs) to solid nodules. However, the dynamic genomic and transcriptomic changes underlying LUAD progression are incompletely understood. Here, we performed whole-genome and transcriptome sequencing on 1008 LUAD samples from 954 patients who underwent surgery at Fudan University Shanghai Cancer Center, with comprehensive follow-up data. There was one atypical adenomatous hyperplasia, 42 adenocarcinomas in situ, 116 minimally invasive adenocarcinomas, and 849 invasive adenocarcinomas spanning all pathological stages. EGFR was the most frequently mutated gene in the study cohort, followed by TP53, RBM10, KRAS, and KMT2D. Mutation frequencies of tumor suppressor genes, such as TP53, RB1, MGA, KEAP1, and STK11, increased as the disease progressed to higher stages. A higher level of genomic instability was seen in LUAD compared with AAH/AIS/MIA samples, characterized by a higher tumor mutation burden, increased somatic copy number alteration burden, and increased structural variation burden. Notably, MAP2K1 E102–I103 deletion was frequently observed in pre-invasive samples, which endowed alveolar type II cells with increased growth potential and initiated tumor formation, suggesting that it is a potential driver mutation of LUAD. In summary, our study highlights key molecular changes during the stepwise progression of LUAD, provides insights into the identification of novel therapeutic targets, and helps to define the curative time window for this disease.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1037-1055"},"PeriodicalIF":25.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01200-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) remains a major therapeutic challenge. Although targeting tumor-specific antigens represents a cornerstone of cancer immunotherapy, current approaches focus predominantly on mutation-derived neoantigens, which offer limited population coverage. Through an integrative analysis of multi-omics data from 279 HCC patients, we demonstrate that aberrant splicing (AS) events occur at a > 59-fold higher frequency than somatic mutations and generate substantially more immunogenic peptides with broader patient applicability (50.94% vs 4.40% population coverage). Focusing on AS transcripts, our stringent selection pipeline identified 34 neoantigens, prioritizing strong immunogenicity for effective vaccine development. Proof-of-concept in vivo experiments demonstrated the efficacy of mRNA vaccines encoding these neoantigens, resulting in significant tumor regression and enhanced intra-tumor infiltration of neoantigen-reactive T cells. We also address the challenge of transporter-associated antigen processing (TAP) deficiency in HCC by proposing the use of TAP-independent AS-derived neoantigens to circumvent immune evasion. Our findings establish AS as a promising source of neoantigens for off-the-shelf mRNA vaccines in HCC and underscore the need to overcome antigen-presentation barriers for effective immunotherapy.
肝细胞癌（HCC）仍然是一个主要的治疗挑战。虽然靶向肿瘤特异性抗原是癌症免疫治疗的基石，但目前的方法主要集中在突变衍生的新抗原上，这提供了有限的人群覆盖。通过对279例HCC患者的多组学数据的综合分析，我们发现异常剪接（AS）事件发生的频率比体细胞突变高50 - 59倍，并且产生更多的免疫原性肽，具有更广泛的患者适用性（50.94% vs 4.40%的人群覆盖率）。专注于AS转录本，我们严格的筛选管道确定了34种新抗原，优先考虑强免疫原性，以开发有效的疫苗。体内概念验证实验证明了编码这些新抗原的mRNA疫苗的有效性，导致肿瘤显著消退，并增强肿瘤内新抗原反应性T细胞的浸润。我们还通过提出使用TAP独立的as衍生新抗原来规避免疫逃避，解决了HCC中转运蛋白相关抗原加工（TAP）缺陷的挑战。我们的研究结果表明，AS是HCC现成mRNA疫苗的一个有希望的新抗原来源，并强调了克服抗原呈递障碍以进行有效免疫治疗的必要性。
{"title":"Harnessing alternative splicing for off-the-shelf mRNA neoantigen vaccines in hepatocellular carcinoma","authors":"Haichao Zhao, Yifei Cheng, Tiancheng Zhang, Qianxi Wang, Yanan Xu, Ganggang Wang, Yuanli Song, Hang Chen, Yingcheng Wu, Mao Zhang, Youpei Lin, Changyou Zhan, Jia Fan, Qiang Gao","doi":"10.1038/s41422-025-01199-0","DOIUrl":"10.1038/s41422-025-01199-0","url":null,"abstract":"Hepatocellular carcinoma (HCC) remains a major therapeutic challenge. Although targeting tumor-specific antigens represents a cornerstone of cancer immunotherapy, current approaches focus predominantly on mutation-derived neoantigens, which offer limited population coverage. Through an integrative analysis of multi-omics data from 279 HCC patients, we demonstrate that aberrant splicing (AS) events occur at a > 59-fold higher frequency than somatic mutations and generate substantially more immunogenic peptides with broader patient applicability (50.94% vs 4.40% population coverage). Focusing on AS transcripts, our stringent selection pipeline identified 34 neoantigens, prioritizing strong immunogenicity for effective vaccine development. Proof-of-concept in vivo experiments demonstrated the efficacy of mRNA vaccines encoding these neoantigens, resulting in significant tumor regression and enhanced intra-tumor infiltration of neoantigen-reactive T cells. We also address the challenge of transporter-associated antigen processing (TAP) deficiency in HCC by proposing the use of TAP-independent AS-derived neoantigens to circumvent immune evasion. Our findings establish AS as a promising source of neoantigens for off-the-shelf mRNA vaccines in HCC and underscore the need to overcome antigen-presentation barriers for effective immunotherapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"970-986"},"PeriodicalIF":25.9,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1038/s41422-025-01198-1
Edvinas Jurgelaitis, Evelina Zagorskaitė, Aurimas Kopūstas, Simonas Asmontas, Elena Manakova, Indrė Dalgėdienė, Ugnė Tylenytė, Arunas Silanskas, Paulius Toliusis, Algirdas Grybauskas, Marijonas Tutkus, Česlovas Venclovas, Mindaugas Zaremba
Present in all three domains of life, Argonaute proteins use short oligonucleotides as guides to recognize complementary nucleic acid targets. In eukaryotes, Argonautes are involved in RNA silencing, whereas in prokaryotes, they function in host defense against invading DNA. Here, we show that SPARDA (short prokaryotic Argonaute, DNase associated) systems from Xanthobacter autotrophicus (Xau) and Enhydrobacter aerosaccus (Eae) function in anti-plasmid defense. Upon activation, SPARDA nonspecifically degrades both invader and genomic DNA, causing host death, thereby preventing further spread of the invader in the population. X-ray structures of the apo Xau and EaeSPARDA complexes show that they are dimers, unlike other apo short pAgo systems, which are monomers. We show that dimerization in the apo state is essential for inhibition of XauSPARDA activity. We demonstrate by cryo-EM that activated XauSPARDA forms a filament. Upon activation, the recognition signal of the bound guide/target duplex is relayed to other functional XauSPARDA sites through a structural region that we termed the “beta-relay”. Owing to dramatic conformational changes associated with guide/target binding, XauSPARDA undergoes a “dimer–monomer–filament” transition as the apo dimer dissociates into the guide/target-loaded monomers that subsequently assemble into the filament. Within the activated filament, the DREN nuclease domains form tetramers that are poised to cleave dsDNA. We show that other SPARDAs also form filaments during activation. Furthermore, we identify the presence of the beta-relay in pAgo from all clades, providing new insights into the structural mechanisms of pAgo proteins. Taken together, these findings reveal the detailed structural mechanism of SPARDA and highlight the importance of the beta-relay mechanism in signal transduction in Argonautes.
{"title":"Activation of the SPARDA defense system by filament assembly using a beta-relay signaling mechanism widespread in prokaryotic Argonautes","authors":"Edvinas Jurgelaitis, Evelina Zagorskaitė, Aurimas Kopūstas, Simonas Asmontas, Elena Manakova, Indrė Dalgėdienė, Ugnė Tylenytė, Arunas Silanskas, Paulius Toliusis, Algirdas Grybauskas, Marijonas Tutkus, Česlovas Venclovas, Mindaugas Zaremba","doi":"10.1038/s41422-025-01198-1","DOIUrl":"10.1038/s41422-025-01198-1","url":null,"abstract":"Present in all three domains of life, Argonaute proteins use short oligonucleotides as guides to recognize complementary nucleic acid targets. In eukaryotes, Argonautes are involved in RNA silencing, whereas in prokaryotes, they function in host defense against invading DNA. Here, we show that SPARDA (short prokaryotic Argonaute, DNase associated) systems from Xanthobacter autotrophicus (Xau) and Enhydrobacter aerosaccus (Eae) function in anti-plasmid defense. Upon activation, SPARDA nonspecifically degrades both invader and genomic DNA, causing host death, thereby preventing further spread of the invader in the population. X-ray structures of the apo Xau and EaeSPARDA complexes show that they are dimers, unlike other apo short pAgo systems, which are monomers. We show that dimerization in the apo state is essential for inhibition of XauSPARDA activity. We demonstrate by cryo-EM that activated XauSPARDA forms a filament. Upon activation, the recognition signal of the bound guide/target duplex is relayed to other functional XauSPARDA sites through a structural region that we termed the “beta-relay”. Owing to dramatic conformational changes associated with guide/target binding, XauSPARDA undergoes a “dimer–monomer–filament” transition as the apo dimer dissociates into the guide/target-loaded monomers that subsequently assemble into the filament. Within the activated filament, the DREN nuclease domains form tetramers that are poised to cleave dsDNA. We show that other SPARDAs also form filaments during activation. Furthermore, we identify the presence of the beta-relay in pAgo from all clades, providing new insights into the structural mechanisms of pAgo proteins. Taken together, these findings reveal the detailed structural mechanism of SPARDA and highlight the importance of the beta-relay mechanism in signal transduction in Argonautes.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1056-1078"},"PeriodicalIF":25.9,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dysregulated metabolism in tumor tissues and para-tumor tissues alike can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib, which specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinoma (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity toward HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We also found that HCC tissues in aldometanib-treated mice were massively infiltrated with CD8+ T cells, which was not seen in mice with liver-specific knockout of AMPKα. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make cancer a lifelong manageable disease may usher in a new era of cancer therapy.
{"title":"Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages","authors":"Hui-Hui Hu, Xuefeng Wang, Bin Lan, Haili Cheng, Hong Wen, Fangfang Chen, Jianfeng Wu, Mengqi Li, Jiazhou Chen, Jinhui Zhang, Dongxu Chen, Shiyu Lin, Jieyu Lin, Mingyang Yang, Zhenhua Wu, Zhong-Zheng Zheng, Fuqing Chen, Jianyin Zhou, Gang Chen, Yu Chen, Xianming Deng, Chen-Song Zhang, Jingfeng Liu, Sheng-Cai Lin","doi":"10.1038/s41422-025-01195-4","DOIUrl":"10.1038/s41422-025-01195-4","url":null,"abstract":"Dysregulated metabolism in tumor tissues and para-tumor tissues alike can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib, which specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinoma (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity toward HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We also found that HCC tissues in aldometanib-treated mice were massively infiltrated with CD8+ T cells, which was not seen in mice with liver-specific knockout of AMPKα. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make cancer a lifelong manageable disease may usher in a new era of cancer therapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"934-953"},"PeriodicalIF":25.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01195-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s41422-025-01201-9
Cell Research Editorial Team
{"title":"Sanofi-Cell Research outstanding paper award of 2024","authors":"Cell Research Editorial Team","doi":"10.1038/s41422-025-01201-9","DOIUrl":"10.1038/s41422-025-01201-9","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"921-921"},"PeriodicalIF":25.9,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01201-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1038/s41422-025-01197-2
Martina Wallace, Ramya S Kuna, Christian M Metallo
{"title":"Branched-chain fatty acids fire up the peroxisome.","authors":"Martina Wallace, Ramya S Kuna, Christian M Metallo","doi":"10.1038/s41422-025-01197-2","DOIUrl":"https://doi.org/10.1038/s41422-025-01197-2","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.
目前免疫疗法的有限成功强调需要新的靶点和联合治疗。V-domain Ig suppressor of T cell activation （VISTA）是肿瘤免疫治疗中一个很有前景的免疫检查点靶点，但其调控机制尚不清楚。通过CRISPR敲除筛选和蛋白质组学分析，我们确定tripartite motif containing 25 （TRIM25）主要通过拮抗其降解信号传导而成为VISTA的正调控因子。此外，erk介导的VISTA Thr284位点磷酸化增强了它与TRIM25的相互作用，导致VISTA稳定。VISTA衍生的磷酸化肽竞争性地破坏TRIM25-VISTA相互作用，从而降低VISTA表达并增强PD-1/PD-L1阻断的抗肿瘤功效。此外，单细胞RNA测序分析显示，在T细胞特异性敲除Trim25的小鼠中，肿瘤浸润性细胞毒性CD8+ T细胞增加。值得注意的是，基因消融T细胞中的Trim25不仅可以改善抗pd - l1免疫治疗，还可以显著改善各种小鼠肿瘤模型中的CAR - T抗肿瘤活性。总的来说，这项研究揭示了VISTA在T细胞中的调节机制，并强调靶向TRIM25-VISTA是增强肿瘤免疫治疗的潜在策略。
{"title":"Destruction of VISTA by TRIM25 ablation in T cells potentiates cancer immunotherapy","authors":"Yishuang Sun, Zijian Zhang, Haiou Li, Xia Bu, Li Chen, Xiyong Wang, Lifang Fan, Baoxiang Chen, Lijun Kong, Panpan Dai, Wenjing Song, Xiangling Xiao, Jie Shi, Bolin Xiang, Chuan He, Yingmeng Yao, Wenjun Xiong, Haisheng Yu, Congqing Jiang, Qun Qian, Hudan Liu, Sufang Tian, Guoliang Qing, Zhiyong Yang, Wenyi Wei, Gordon J. Freeman, Haichuan Zhu, Jinfang Zhang","doi":"10.1038/s41422-025-01186-5","DOIUrl":"10.1038/s41422-025-01186-5","url":null,"abstract":"The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 12","pages":"1003-1020"},"PeriodicalIF":25.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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