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