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Significance Hepatocellular carcinoma (HCC), a type of liver cancer, has a poor 5-y survival rate and current therapies provide only marginal clinical benefits to most HCC patients. Therefore, new therapeutic approaches are needed for HCC treatment. Natural killer (NK) cells are cells of the innate immune system that can inhibit tumor development and progression. We find that pharmacological inhibition of EZH2 results in NK cell–mediated hepatic tumor growth inhibition in mice, which occurs, in part, due to the increased expression of the chemokine CXCL10, leading to increased NK cell migration. These results have implications for EZH2-dependent tumors, in which NK cell–mediated tumor clearance can be induced using EZH2 inhibitors.

EZH2 inhibits NK cell–mediated antitumor immunity by suppressing CXCL10 expression in an HDAC10-dependent manner