Xiaojun Yan 1, Wenbin Xu 1, Han Yao 1, Zhen Wu 1, Jingyuan Ning 1, Shidong Zhao 2, Yajing Liu 1, Meng Zhang 1, Dongkui Xu 3, Zhanlong Shen 2, Wei Gu 4, Donglai Wang 1

Cancer Discov. 2026 Jan 12;16(1):155-176.

PMID: 40970761 DOI: 10.1158/2159-8290.CD-25-0649

Abstract

Although p53 plays a central role in tumor suppression, how it is regulated in T cells to exert antitumor effects remains unclear. In this study, 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.

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