Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma [Spatial Transcriptomics]

Here, we employed spatial and single-cell transcriptomics to reveal a role for Nur77 in NK cell-mediated immunity against hepatocellular carcinoma (HCC). The expression of NR4A1, encoding Nur77, is associated with NK cell proliferation, activation of the immunostimulatory AP-1 gene regulons and better disease-free survival in HCC.

Conditional ablation of Nr4a1 in NK cells perturbed their homeostasis and accelerated tumor progression in multiple tumor models while the agonistic activation of Nur77 in NK cells ex-vivo or in-vivo enhanced their anti-tumor functions. Mechanistically, Nur77 activation attenuated CD36 expression in NK cells and conferred resistance against oxLDL-mediated immunosuppression in the TME. Collectively, our findings highlighted the potential of harnessing Nur77 agonism in improving NK cell-based immunotherapy against tumors.