DNA sensing through the cGAS-STING pathway plays an important role in cancer immunosurveillance. Pharmaceutical activation of STING in the tumor environment is considered an attractive approach to induce anti-tumor immunity, but had limited efficacy in the clinic. Several studies have found that STING is epigenetically silenced in many tumors, including colon cancer. This suggests that STING silencing in tumor cells contributes to immune escape and may limit the application of STING agonists. We previously found that inhibition of the KDM5 family histone demethylases restored STING expression in human breast cancer cells and activated the cGAS-STING pathway. In this study, we used MC38 and CT26 syngeneic mouse colorectal cancer models to show that loss of STING in tumor cells accelerates tumor growth. KDM5 inhibitors activate STING expression in mouse colorectal cancer cells and suppress colon cancer growth in immune competent mice in a STING-dependent manner. This study highlights KDM5 inhibitors as novel immune modulators in cancer therapies.