Loss of EHMT2 enhances NK cell-driven anti-tumor immunity through TGF-β1 suppression

Abstract Natural Killer (NK) cells play a critical role in regulating tumor growth, but our understanding of the mechanisms underlying their anti-tumor activity remains limited. We identified the histone methyltransferase EHMT2 as a key suppressor of NK cell-mediated cytotoxicity. EHMT2 inhibition in cancer cells enhanced NK cell-mediated elimination of diverse cancers, including uveal melanoma, breast cancer, and pancreatic cancer. EHMT2 loss increased AZGP1 and decreased TGF-β1 levels, resulting in the autocrine elevation of NKG2D ligands MICB and ULBP3, chemokines in cancer cells, and the paracrine stimulation of NK cell function. In a syngeneic pancreatic cancer model, EHMT2 inhibition suppressed tumors in an NK cell-dependent manner, as NK cell depletion restored tumor growth. This effect persisted and remained dependent on NK cells in Rag2 knockout mice (lacking T and B cells), but not in NSG mice (lacking T-, B- and NK-cells). Furthermore, EHMT2 and TGF-β1 inhibitors suppressed tumors in immunocompetent, but not in immunodeficient mice. These findings establish EHMT2 as a suppressor of NK cell-mediated anti-tumor immunity and a promising therapeutic target.