2025/12/09 by Suresh Chava, Suresh Bugide, Parmanand Malvi +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #Cancer-related Molecular Pathways #Histone Deacetylase Inhibitors Research #Immune Cell Function and Interaction
paper · doi:10.1038/s44321-025-00357-6
openalex created_date 2025/12/09 · openalex publication_date 2025/12/09 · openalex updated_date 2026/07/23
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.