Pharmacological rescue of mutant p53 triggers spontaneous tumor regression via immune responses

Tumor suppressor p53 is the most frequently mutated protein in cancer, possessing untapped immune-modulating capabilities in anticancer treatment. Here, we investigate the efficacy and underlying mechanisms of pharmacological reactivation of mutant p53 in treating spontaneous tumors in mice. In the p53 R279W (equivalent to the human hotspot R282W) mouse model developing spontaneous tumors, arsenic trioxide (ATO) treatment through drinking water significantly prolongs the survival of mice, dependent on p53-R279W reactivation. Transient regressions of spontaneous T-lymphomas are observed in 70% of the ATO-treated mice, accompanied by interferon (IFN) response. In allograft models, the tumor-suppressive effect of reactivated p53-R279W is detectably reduced in both immunodeficient Rag1 −/− and CD8 + T cell-depleted mice. ATO also activates the IFN pathway in human cancer cells harboring various p53 mutations, as well as in primary samples derived from the p53-mutant patient treated with ATO. Together, p53 could serve as an alternative therapeutic target for the development of immunotherapies. • ATO triggers spontaneous tumor regression and extends survival of p53-mutant mice • CD8 + T cells and IFN-γ are crucial for ATO-induced tumor regression • ATO triggers IFN signaling in p53-mutant cancer cell lines and primary cancer cells Li et al. explore the potential of pharmacological reactivation of mutant p53 in cancer treatment, showing that it effectively induces tumor regression and extends survival by restoring classic p53 tumor-suppressive functions and activating immune responses in mice, offering insights for tumor suppressor-based cancer immunotherapy.