Antagonistic roles of histone 3 lysine methyltransferases dictate tumor immune surveillance

Using KRAS-driven lung cancer models, we show that NSD2, SETD2, and EZH2 form an epigenetic circuit that regulates endogenous retroviral elements (ERVs) and tumor immune surveillance. Although SETD2 is a potent tumor suppressor in KRAS-driven lung adenocarcinoma, expression of the H3K36M oncohistone, which broadly inhibits H3K36 methylation, does not phenocopy Setd2 loss.

Instead, H3K36M expression suppresses tumor growth by reducing H3K36me2, derepressing ERV transcripts, inducing cytoplasmic dsRNA, and activating RIG-I/MDA5-dependent antiviral-like immune clearance. Genetic inactivation of histone dimethyltransferase Nsd2 phenocopies H3K36M expression, nominating H3K36me2 loss as a trigger of this viral-mimicry response. In Setd2-deficient contexts, EZH2-dependent H3K27me3 restores ERV repression, prevents dsRNA accumulation, and permits immune escape.