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

TP53-mutant acute myeloid leukemia (AML) is associated with particularly poor clinical outcomes and resistance to current therapies. While immunotherapy has revolutionized treatment for other hematologic malignancies, its efficacy in TP53-mutant AML remains limited. Although TP53 mutations in leukemic blasts are well characterized, their presence and functional consequences in immune cells have not been fully explored. Here we show that TP53 mutations are also present in T and NK cells from AML patients, where they are associated with increased activation markers but diminished cytotoxic function. T cells engineered to express common TP53 mutations exhibit an exhausted phenotype, characterized by impaired cytokine secretion and reduced tumor-killing capacity. Remarkably, restoring wild-type p53 conformation using a targeted small molecule reactivator reverses these dysfunctions and improves disease control in preclinical AML models. These findings reveal a novel mechanism of immune escape driven by mutant p53 in T cells and highlight the therapeutic potential of p53 reactivation. This work broadens our understanding of immune dysfunction in AML and supports incorporating immune-cell genotyping and correction strategies into future immunotherapy approaches for TP53-mutant disease.