Nuclear receptor Nur77 is a transcription factor with immunomodulatory functions. Here, by integrating patient-derived samples, organoid co-cultures, and mouse models of hepatocellular carcinoma, the authors show that Nur77 promotes NK cell maturation and cytotoxicity by reducing lipid-mediated suppression and upregulating AP-1 response gene, and that Nur-77 agonism improves the response to adoptive NK cell therapy in HCC preclinical mouse models.