Vaccines targeting p53 mutants elicit anti-tumor immunity

The p53 tumor suppressor is commonly mutated in cancer; however, there are no effective treatments targeting p53 mutants. A DNA vaccine gWIZ-S237G targeting the p53 S237G mutant, which is highly expressed in A20 murine tumor cells, was developed and administered intramuscularly via electroporation, either alone or in combination with PD-1 blockade. The anti-p53-S237G immunization elicited a robust protective response against subcutaneous A20 tumors and facilitated the infiltration of immune cells including CD8⁺ T cells, NK cells, and DCs. The vaccine enhanced the induction and maturation of CD11c⁺, CD103⁺CD11c⁺, and CD8⁺CD11c⁺ cells, which in turn promoted tumor-specific antibody production, as well as Th1 and CD8⁺ T cell-mediated immune responses. Several antigenic epitopes of p53-S237G effectively stimulated multifunctional CD8⁺ T cells to secrete IFN-γ and TNF-α. The vaccine showed long-term anti-tumor effects that were dependent on memory CD8⁺ T cells. Furthermore, the anti-p53-S237G vaccine exhibited significant protective efficacy in the A20 liver metastasis models. When combined with PD-1 inhibition, the vaccine showed superior inhibition of tumor growth and liver metastasis. Targeting p53 mutants by vaccination represents a potential precision medicine strategy against cancers harboring p53 mutations.