{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE333nnn/GSE333664/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by array"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE333664"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"EHMT1/2 knockout induces a broad interferon signature","description":"Epigenetic 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.","dates":{"publication":"2026/06/08"},"accession":"GSE333664","cross_references":{"GSM":["GSM9770590","GSM9770591","GSM9770592","GSM9770593","GSM9770598","GSM9770599","GSM9770588","GSM9770589","GSM9770594","GSM9770595","GSM9770596","GSM9770597"],"GPL":["27956"],"GSE":["333664"],"taxon":["Homo sapiens"]}}