GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE333nnn/GSE333664/primaryOK200TranscriptomicsHomo sapiensExpression profiling by arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE333664GEOGSEfalseEHMT1/2 knockout induces a broad interferon signatureEpigenetic silencing of interferon (IFN) signaling contributes to the profound resistance of “immune-cold” tumors to PD-1/PD-L1 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. We then developed TNG917, a histone substrate-competitive dual inhibitor of EHMT1/2 with superior, low-nanomolar potency in cells and high selectivity over other methyl transferases. 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 novel strategy to convert immune-cold tumors into T-cell-inflamed lesions and potentiate checkpoint blockade, supporting its advancement into clinical development in combination immunotherapy.2026/06/08GSE333664GSM9770590GSM9770591GSM9770592GSM9770593GSM9770598GSM9770599GSM9770588GSM9770589GSM9770594GSM9770595GSM9770596GSM977059727956333664Homo sapiens