mTORC1 Suppression by Trp53 Mutation Drives Resistance to Immune Checkpoint Blockade

p53 is a critical tumor suppressor gene that inhibits cancer development by regulating cell cycle arrest, apoptosis, DNA repair, and metabolism. However, recent studies examining TP53 mutations in cancer immunotherapy have yielded inconsistent results, likely due to differences in tumor mutational burden (TMB) and the context-dependent roles of specific p53 mutants. In this study, we assessed the function of G242V and S258I Trp53 mutations in MC38 cells in the context of immunotherapy by generating Trp53 deletion and observed significantly enhanced responses to anti-PD-1 therapy. Trp53 -null tumors showed increased CD8 ⁺ T cell infiltration and clonal expansion, along with reduced regulatory T (Treg) cells. Mechanistically, Trp53 deletion downregulated mTORC1 inhibitor genes, leading to elevated mTORC1 signaling and diminished autophagy, which sensitized tumor cells to IFN-γ and TNF-α-induced apoptosis. Besides mouse cells, we confirmed the human p53 mutants regulate the same sets of mTORC1 inhibitor genes in a human colorectal cancer cell line. Our findings demonstrate that certain p53 mutants, despite losing other canonical functions, retain wild-type p53’s ability to suppress mTORC1 and enhance autophagy, thereby inhibiting responses to immunotherapy.