biostudies-literatureChava SHHS | National Institutes of Health (NIH)NCI NIH HHSDOD | Department of Defense Education Activity (DoDEA)232-274https://www.ebi.ac.uk/biostudies/studies/S-EPMC12808752biostudies-literatureUnknown18(1)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 persEMBO molecular medicineLoss of EHMT2 enhances NK cell-driven anti-tumor immunity through TGF-β1 suppression.PMC12808752F31 CA271673R00CA241110R01CA271673R00 CA241110HT9425-24-1-0593Gupta RWajapeyee NMa BMalvi PDeMarco KDBugide SRuscetti MZajac AChava SParikh CNCai GfalseLoss of EHMT2 enhances NK cell-driven anti-tumor immunity through TGF-β1 suppression.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 pers2026-01-01T00:00:00Z2026 Jan2026-06-12T04:52:21.325Z2026-06-12T03:07:44.676ZS-EPMC128087524136652010.1038/s44321-025-00357-6