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

Abstract

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.