EHMT1/2 knockout induces a broad interferon signature

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.