biostudies-literatureLi YNIDCR NIH HHSNIDDK NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHS3901-3918.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC9588679biostudies-literatureUnknown82(20)How cancer-associated chromatin abnormalities shape tumor-immune interaction remains incompletely understood. Recent studies have linked DNA hypomethylation and de-repression of retrotransposons to anti-tumor immunity through the induction of interferon response. Here, we report that inactivation of the histone H3K36 methyltransferase NSD1, which is frequently found in squamous cell carcinomas (SCCs) and induces DNA hypomethylation, unexpectedly results in diminished tumor immune infiltration. In syngeneic and genetically engineered mouse models of head and neck SCCs, NSD1-deficient tumors exhibit immune exclusion and reduced interferon response despite high retrotransposon expression. Mechanistically, NSD1 loss results in silencing of innate immunity genes, including the type III interferMolecular cellHistone methylation antagonism drives tumor immune evasion in squamous cell carcinomas.PMC9588679R01 CA272901P01 CA196539R01 DE031873P30 CA013696S10 OD020056R01 CA197774R35 GM138181R37 CA258829R01 CA227450R35 GM118015R01 DK132251R01 CA266978R21 CA263381Farhangdoost NHorth CAilles LQue JMendelsohn CLLu CMcGuire JTCiccia ALeuzzi GLi YIzar BLi ZZhang ZTate TYoon AJDai EGoldberg EMChen XKaragiannis DXu XMajewski JfalseHistone methylation antagonism drives tumor immune evasion in squamous cell carcinomas.How cancer-associated chromatin abnormalities shape tumor-immune interaction remains incompletely understood. Recent studies have linked DNA hypomethylation and de-repression of retrotransposons to anti-tumor immunity through the induction of interferon response. Here, we report that inactivation of the histone H3K36 methyltransferase NSD1, which is frequently found in squamous cell carcinomas (SCCs) and induces DNA hypomethylation, unexpectedly results in diminished tumor immune infiltration. In syngeneic and genetically engineered mouse models of head and neck SCCs, NSD1-deficient tumors exhibit immune exclusion and reduced interferon response despite high retrotransposon expression. Mechanistically, NSD1 loss results in silencing of innate immunity genes, including the type III interfer2022-01-01T00:00:00Z2022 Oct2026-05-28T01:35:52.553Z2025-02-19T03:05:36.077ZS-EPMC95886793620676710.1016/j.molcel.2022.09.007