Histone H3 lysine 36 (H3K36) methyltransferases are frequently mutated in cancer, but their functional roles remain unclear. Using functional genomics approaches within KRAS-driven lung cancer models, we show that NSD2, SETD2, and EZH2 work in concert to regulate expression of endogenous retroviral elements, which act as a molecular rheostat controlling immune surveillance. Specifically, loss of H3K36me2 and H3K36me3 activity through H3K36M oncohistone expression or H3K36me2 alone through NSD2 inactivation leads to derepression of endogenous retroviral element transcripts that activate a dsRNA-mediated antiviral-like immune response that potently eradicates KRAS-driven tumor growth. Surprisingly, derepression of ERV sequences and subsequent immune reactions are completely dependent on SETD2, a tumor suppressor in KRAS-driven lung cancer that directly mediates H3K36me3 deposition. Mechanistically, inactivation of both NSD2 and SETD2 attenuates immune reactions by activating EZH2-dependent H3K27me3 and transcript repression at ERV sequences. These findings define an enzymatic triad of NSD2, SETD2, and EZH2 whose coordinated activities link chromatin regulation and tumor immune surveillance, revealing new epigenetic vulnerabilities in cancer.