Discovery of a therapeutic antibody for p53 high-frequency mutations in pan-cancer

The tumor suppressor p53 is the most frequently mutated gene in human cancers, yet therapeutically targeting its diverse mutant forms remains a major challenge. Here, we developed a conformation-specific monoclonal antibody, P20-mAb, that selectively recognized a broad spectrum of p53 hotspot mutations without cross-reactivity to wild-type p53. Delivered via lipid nanoparticles (LNPs), P20-mAb accumulated in p53-mutant tumors and triggered potent anti-tumor immunity by activating natural killer (NK) cells and promoting CD8+ T cell dependent responses. Furthermore, P20-mAb remodeled the tumor microenvironment by enhancing dendritic cell (DC) crosstalk with NK and CD8+ T cells, upregulating MHC-I antigen presentation, expanding tumor-specific cytotoxic CD8+ T cells, and enriching antigen-reactive TCR clonotypes. Compared to a mutation-specific antibody targeting p53-R175H, P20-mAb exhibited broader tumor recognition, more robust activation of innate and adaptive immune compartments, and stronger expansion of functional CD8+ T cells. In humanized mouse models, P20-mAb suppressed the growth of diverse p53-mutant tumors with superior breadth and efficacy. These findings establish P20-mAb as a broadly reactive, immune-potentiating antibody with therapeutic potential for precision immunotherapy in p53-driven cancers.