Activation of T Cell-Intrinsic p53 by Acetylation Elicits Antitumor Immunity to Boost Cancer Immunotherapy.

[UNLABELLED] 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.

[SIGNIFICANCE] This study identifies T cell-intrinsic p53 as a key determinant of immunotherapy efficacy. CTD acetylation, rather than stabilization, activates a p53-IFN-γ feedback loop and promotes CD8+ T cell-mediated antitumor immunity independently of tumor p53 status. These findings reveal a non-tumor cell-autonomous action of p53 to boost PD-1-based immunotherapy.