A recent RNAi screen targeting 565 known epigenetic/chromatin regulators identifies DNMT1 synthetic lethality with PRC2 inactivation in MPNST.659 Mechanistically, PRC2 inactivation enhances DNMT inhibition-mediated activation of retrotransposons and subsequent viral mimicry response.659 DNMT and EZH2 inhibitors synergize to amplify antitumor immune response in hepatocellular carcinoma with wild-type EZH2,717 consolidating DNMT1-targeted therapy can be used to treat PRC2-loss cancer. The gene discussed is EZH2; the disease is hepatocellular carcinoma.