Pyrithione zinc alters mismatch repair to trigger tumor immunogenicity

Mismatch repair deficiency (dMMR) cancers are highly sensitive to immunotherapy, but only account for a small fraction of cancer patients. How to increase immunotherapy efficacy on MMR-proficient (pMMR) cancer is still a major challenge. This study demonstrates that pyrithione zinc (PYZ), an FDA-approved drug, can enhance tumor immunogenicity via altering MMR and activating STING signaling. Mechanistically, PYZ elevates levels of ROS, leading to the upregulation of HIF-1α and DNA damage, while also inhibiting the expression of DNA mismatch repair proteins MSH2 and MSH6, together promoting DNA damage accumulation. Therefore, the administration of PYZ results in the accumulation of DNA damage, leading to the activation of STING signaling, which enhances tumor immunogenicity. Knockout of Sting diminishes the activation of IFN-I signaling induced by PYZ and reduces tumor immunogenicity. Furthermore, in vivo administration of PYZ promotes the infiltration of CD8⁺ T cells into the tumor and inhibits tumor growth, an effect that is attenuated in Nude mice or mice with CD8⁺ T cell depletion or deficiency of Ifnar. Overall, our findings showed that pyrithione zinc could trigger tumor immunogenicity by downregulating MMR machinery and activating STING pathway in tumor cells, and provide a translational approach to improve immunotherapy on pMMR cancer.