Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors.