While there is considerably large spectrum of various inhibitory receptors possibly expressed by T and NK cells, there are limited transcriptional regulators that potently drives immune exhaustion such as proteins within the NR4A family. Nur77 expression in NK cells was recently associated with early antigenic response to cytomegalovirus. However, it remains unknown how Nur77 (NR4A1) influence NK cell functionality. Present study sought to determine how Nur77 influence NK cell-mediated immunity against hepatocellular carcinoma (HCC). Digital spatial profiling of HCC tissue microarray uncovers a unique gene signature that is associated with Nur77+ immune cells and at the same time, prognostic for better patient survival. Furthermore, majority of the genes in this spatial signature was found upregulated by Nur77+ NK cells as determined by subsequent single cell sequencing of a separate patient cohort. Additionally, these Nur77+ NK cells was associated with higher scores of AP-1 gene regulatory networks. Likewise, Nur77 was similarly associated with favorable NK cell phenotypes as determined in breast and ovarian cancer cohorts. To determine the role of Nur77 in vivo, we generated a conditional knockout mice for the depletion of Nur77 in NK cells (NCR1^iCRE, NR4A1^fl/fl) to confirm impaired anti-tumor immunity in RMA-S and orthotopic HCC models. On the other hand, the use of a Nur77 agonist, Cytosporone B, enhances NK cell-mediated immunity in multiple tumor mice models. Mechanistically, we found that Nur77 is associated with lower CD36 expression, conferring protection against ferroptosis or immunosuppression mediated by lipid peroxides. Taken together, our collective findings provide strong rationale for Nur77 agonism to improve existing NK cell therapies for targeting solid tumors.