NR4A1 mediates NK‐cell dysfunction in hepatocellular carcinoma via the IFN‐γ/p‐STAT1/IRF1 pathway

Abstract Hepatocellular carcinoma (HCC) is one of the most fatal tumours worldwide and has a high recurrence rate. Nevertheless, the mechanism of HCC genesis remains partly unexplored, while the efficiency of HCC treatments remains limited. The present study analysed the expression of nuclear receptor subfamily 4 group A member 1 (NR4A1) in tumour‐infiltrating natural killer (NK) cells derived from both human patients with HCC and tumour‐bearing mouse models, as well as the features of NR4A1 high and NR4A1 low NK cells. In addition, knockout of NR4A1 by CRISPR/Cas9 and adoptive transfer experiments were applied to verify the function of NR4A1 in both tumour‐infiltrating NK cells and anti‐PD‐1 therapy. The present study found that NR4A1 was significantly highly expressed in tumour‐infiltrating NK cells, which mediated the dysfunction of tumour‐infiltrating NK cells by regulating the IFN‐γ/p‐STAT1/IRF1 signalling pathway. Knockout of NR4A1 in NK cells not only restored the antitumour function of NK cells but also enhanced the efficacy of anti‐PD‐1 therapy. The present findings suggest a regulatory role of NR4A1 in the immune progress of NK cells against HCC, which may provide a new direction for immunotherapies of HCC.