Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy

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.