Somatic TP53 Mutations Drive T and NK Cell Dysfunction in AML and Can be Rescued by Reactivating Wild Type p53

Therapeutic advances in immunotherapy have significantly improved outcomes in lymphomas and myelomas, yet patients with TP53-mutant acute myeloid leukemia (AML) continue to be challenged. While TP53 mutations in leukemic blasts have been extensively characterized, their incidence and impact within immune cells remain largely unexplored. Here, using single-cell multi-omics and integrated phenotypic analyses, we identify TP53 mutations in T and NK cells from AML patients. Notably, T cells harboring monoallelic TP53 mutations exhibited elevated proliferative markers yet showed reduced cytotoxic capacity and increased expression of inhibitory receptors, including PD-1, TIGIT, and TIM-3. To investigate the functional consequences of p53-mutant immune cells, we engineered CAR-T cells carrying clinically relevant p53 mutations (Y220C and R175H). These mutant p53 CAR-T cells exhibited a pronounced exhaustion phenotype, with diminished cytokine secretion and impaired tumor cytolysis both in vitro and in PDX mouse models. Crucially, restoring mutant p53 to a wild-type conformation using a targeted small-molecule reactivator rescued CAR-T functionality, reduced exhaustion marker expression, and prolonged survival in AML PDX mouse models, revealing a direct mechanistic link between TP53 mutations in T cells and therapeutic resistance. Our findings establish TP53-mutant T cells as a previously unrecognized driver of immune escape in AML, highlighting the importance of immune-cell genotyping and p53 reactivation strategies. By demonstrating that mutant p53 can be selectively corrected to restore T-cell function, this study opens new avenues for immunotherapeutic intervention in TP53-mutant AML.