Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance

Abstract SETD2 is a critical tumor suppressor in lung cancer that catalyzes histone H3 lysine 36 (H3K36) trimethylation. Oncogenic histone H3 alleles, including H3 K36M , causally drive cancer formation by dominantly inhibiting SETD2 and other H3K36 methyltransferases. Here we show that expression of the H3 K36M oncogene paradoxically suppresses tumor growth in KRAS-driven lung cancer by promoting transcription of repetitive elements and accumulation of cytoplasmic dsRNA, activating antiviral-like immune clearance. Unexpectedly, all attendant effects of H3 K36M expression require SETD2 activity despite widespread loss of H3K36 trimethylation. Reducing H3K36 dimethylation through genetic or pharmacologic attenuation of NSD2 phenocopies H3 K36M expression, revealing NSD2 as the relevant target through which H3 K36M triggers immune activation. Mechanistically, H3 K36M expression or NSD2 attenuation reveals a SETD2-dependent mechanism that limits EZH2-mediated repression of repetitive elements, enabling dsRNA accumulation and immune activation. These findings establish opposing roles for NSD2- and SETD2-dependent H3K36 methylation in lung tumor immunity and reveal an NSD2–SETD2–EZH2 axis that can be targeted to modulate viral mimicry and immune surveillance in cancer.