Disulfiram/copper triggers cGAS-STING innate immunity pathway via ROS-induced DNA damage that potentiates antitumor response to PD-1 checkpoint blockade.

Abstract

Immune checkpoint blockades (ICBs) have emerged as the leading strategy for treating advanced malignancies; however, their clinical efficacy is frequently constrained by primary or acquired resistance. Harnessing innate immune signaling to increase lymphocyte infiltration into tumors has been recognized a promising approach to augment the anti-cancer immune response to ICBs. Disulfiram (DSF), an FDA-approved drug for chronic alcoholism, has shown potent anti-tumor effect, particularly when used in combination with copper (Cu). Here, we demonstrated a combination treatment of DSF and Cu (DSF/Cu) robustly activated cancer cell-intrinsic cGAS-STING-dependent innate immune signaling pathway. Further studies revealed that DSF/Cu caused mitochondrial and nuclear DNA damage and the release of cytosolic dsDNA by inducing excessive reactive oxygen species (ROS) generation, thereby triggering innate immunity and enhancing anti-tumor effects. Moreover, DSF/Cu significantly increased the intratumoral infiltration of CD8⁺ cytotoxic lymphocytes and natural killer (NK) cells, and potentiated the therapeutic efficacy of PD-1 checkpoint blockade in murine tumor models. Overall, our findings provide a rationale underlying the anti-cancer and immunomodulatory function of DSF/Cu and highlight the potential of repurposing DSF to improve responses to ICBs in cancer patients.