Pharmacological activation of p53 triggers viral mimicry response thereby abolishing tumor immune evasion and promoting anti-tumor immunity.

The repression of repetitive elements is an important facet of p53's function as a guardian of the genome. Paradoxically, we found that p53 activated by MDM2 inhibitors induced the expression of endogenous retroviruses (ERVs) via increased occupancy on ERV promoters and inhibition of two major ERV repressors, histone demethylase LSD1 and DNA methyltransferase DNMT1. Double-stranded RNA stress caused by ERVs triggered type I/III interferons expression and antigen processing and presentation. Pharmacological activation of p53 in vivo unleashed the interferon program, promoted T cell infiltration and significantly enhanced the efficacy of checkpoint therapy in a xenograft tumor model. Furthermore, MDM2 inhibitor ALRN-6924 induced a viral mimicry pathway and tumor inflammation signature genes in melanoma patients. Our results identify ERV expression as the central mechanism whereby p53 induction overcomes tumor immune evasion and transforms tumor microenvironment to a favorable phenotype, providing a rationale for the synergy of MDM2 inhibitors and immunotherapy.