Epigenetic silencing of interferon (IFN) signaling contributes to the resistance of tumors to PD-1/PD-L1 immune checkpoint blockade. In this study, we conducted a fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen to identify tumor-intrinsic regulators of PD-L1 surface expression and identified the histone-lysine methyltransferases EHMT1 and EHMT2 as key suppressors of interferon signaling. TNG917 was developed as a histone substrate-competitive dual inhibitor of EHMT1/2 with low-nanomolar potency in cells and high selectivity over other methyltransferases. In cancer cell lines, TNG917 relieved H3K9-mediated repression, restored interferon-stimulated gene expression, and triggered secretion of T-cell chemoattractant cytokines, including CXCL10. When dosed orally in both syngeneic and humanized mouse models, TNG917 monotherapy led to marked tumor growth inhibition, while combination with anti-PD1 therapy produced complete, durable regressions and established protective immune memory. Early pharmacokinetic and toxicology assessments revealed favorable exposure profiles and a wide safety margin. These findings establish EHMT1/2 inhibition by TNG917 as a strategy to convert immune-cold tumors into T-cell-inflamed lesions and potentiate checkpoint blockade efficacy, supporting its advancement into clinical development in combination with immunotherapy.