ZNF296 Drives Immune Evasion in Epithelial Cancers by Repressing Immune Stimulatory Genes

Resistance to immune-mediated destruction is a fundamental hallmark of Cancer. Although several mechanisms have been identified that facilitate immune evasion, the transcriptional programs that orchestrate this process remain poorly understood. Here, through a genome-wide CRISPR activation screen in human Cancer cells subjected to natural killer (NK) cell-mediated killing, we identified ZNF296, a transcription factor highly expressed in epithelial cancers, as a key driver of tumor resistance to both NK and cytotoxic T cell (CTL)-mediated immunity. In mouse models, inhibition of ZNF296 significantly enhanced both NK and T cell-mediated anti-tumor immunity, leading to a marked reduction in metastasis and increased infiltration of immune cells into the tumor microenvironment. Mechanistically, ZNF296 induced strong transcriptional repression of interferon-stimulated genes and key immunostimulatory ligands critical for NK and T cell-mediated cytotoxicity. At the molecular level, ZNF296 directly interacted with and recruited the NuRD chromatin remodeling and deacetylase complex to the promoters of its target genes to suppress expression. Notably, treatment with low-dose romidepsin, an FDA-approved inhibitor targeting HDAC1, a core component of the NuRD complex, effectively restored NK and T cell-mediated killing in Cancer cells with high ZNF296 expression. Collectively, these findings establish ZNF296 as a key regulator of immune evasion, driving resistance to both NK and T cell-mediated antitumor immunity, and highlight its potential as a therapeutic target to overcome immune resistance in epithelial cancers.