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

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.