Revisiting tumor immunogenicity through the lens of mutant p53: Implications for cancer immunotherapy

The efficacy of cancer immunotherapy depends on the inherent immunogenicity of tumor cells, which is their ability to display recognizable antigens and stimulate effective immune responses. However, the immunogenic landscape of cancer is not static; it evolves through cancer immunoediting, a dynamic process that refines tumor antigenicity and sculpts immune evasion mechanisms. This immunogenic reprogramming often dictates therapeutic responsiveness, with many tumors acquiring immune resistance through defective antigen presentation, impaired interferon signaling, and the establishment of immunosuppressive microenvironments. Within this complex interplay, mutant p53 (mut-p53) has emerged as a pivotal regulator of tumor immunogenicity. Beyond its canonical oncogenic functions, gain-of-function (GOF) and other p53 mutants modulate antigen processing, repress immune-stimulatory pathways, upregulate immune-checkpoint (IC) molecules, and remodel the tumor microenvironment (TME) to favor immune escape. Paradoxically, their structural instability and aberrant accumulation generate tumor-specific neoepitopes, rendering mut-p53 a potential tumor-specific antigen (TSA) with both immunogenic and immunosuppressive properties. Such dual propensity of mut-p53 positions it as a central architect of immune editing and a critical predictor of immunotherapy outcomes. This review amalgamates growing molecular and clinical evidences to elucidate how mut-p53 regulates the immunogenic continuum of malignancies and contributes to foster immunotherapy resistance. Furthermore, this review emphasizes the novel therapeutic prospects of hotspot TP53 mutations in either generating neoantigen vaccines, T cell receptor (TCR)-based therapies, or by pharmacological targeting of mut-p53 to restore immune surveillance, improve antigen presentation, and synergize with immune-checkpoint blockade (ICB). By bridging the conceptual frameworks of tumor immunogenicity and oncogenic signaling, current review highlights mut-p53 as a promising context-dependent biomarker whose predictive value is determined by its interaction with established molecular and immunological determinants of tumor immunogenicity, immune escape, therapeutic resistance, and tumor evolution; thus underscoring its promise as both a biomarker and a therapeutic target in crafting next-generation precision cancer immunotherapy strategies.