{"title":"Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy.","authors":"Xiaojun Yan,Wenbin Xu,Han Yao,Zhen Wu,Jingyuan Ning,Shidong Zhao,Yajing Liu,Meng Zhang,Dongkui Xu,Zhanlong Shen,Wei Gu,Donglai Wang","doi":"10.1158/2159-8290.cd-25-0649","DOIUrl":null,"url":null,"abstract":"Although p53 plays a central role in tumor suppression, how it is regulated in T cells to exert antitumor effects remains unclear. Here, we show that activation of T cell-intrinsic p53 via carboxyl-terminal domain (CTD) acetylation during immunotherapy activates the IFN-γ pathway, promotes CD8+ T cell infiltration, and elicits CD8+ T cell-dependent antitumor immunity. Using T cell-specific knockin mouse models, we demonstrate that loss of CTD acetylation in T cells abrogates CD8+ T cell-dependent antitumor immunity whereas expression of CTD acetylation-mimicking p53 in T cells enhances this immune response. Moreover, we identify IFNG as a direct target of T cell-intrinsic p53 and uncover a positive feedback loop between p53 and the IFN-γ pathway for enhancing T cell-dependent antitumor immunity. Our study reveals that CTD acetylation-mediated activation of T cell-intrinsic p53 promotes antitumor immunity in response to immunotherapy, highlighting a non-tumor cell-autonomous mechanism of p53 action by regulating adoptive immune responses.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"9 1","pages":""},"PeriodicalIF":33.3000,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.cd-25-0649","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Although p53 plays a central role in tumor suppression, how it is regulated in T cells to exert antitumor effects remains unclear. Here, we show that activation of T cell-intrinsic p53 via carboxyl-terminal domain (CTD) acetylation during immunotherapy activates the IFN-γ pathway, promotes CD8+ T cell infiltration, and elicits CD8+ T cell-dependent antitumor immunity. Using T cell-specific knockin mouse models, we demonstrate that loss of CTD acetylation in T cells abrogates CD8+ T cell-dependent antitumor immunity whereas expression of CTD acetylation-mimicking p53 in T cells enhances this immune response. Moreover, we identify IFNG as a direct target of T cell-intrinsic p53 and uncover a positive feedback loop between p53 and the IFN-γ pathway for enhancing T cell-dependent antitumor immunity. Our study reveals that CTD acetylation-mediated activation of T cell-intrinsic p53 promotes antitumor immunity in response to immunotherapy, highlighting a non-tumor cell-autonomous mechanism of p53 action by regulating adoptive immune responses.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.