Hepatocellular carcinoma (HCC) remains an important complication of chronic liver disease, especially when cirrhosis occurs. Existing treatment strategies include surgery, loco-regional techniques, and chemotherapy. Natural killer cells are distinctive cytotoxic lymphocytes that play a vital role in fighting tumors and infections. As an important constituent of the innate immune system against cancer, phenotypic and functional deviations of NK cells have been demonstrated in HCC patients who also exhibit perturbation of the NK-activating receptor/ligand axis. The rate of recurrence of tumor-infiltrating and circulating NK cells are positively associated with survival benefits in HCC and have prognostic significance, suggesting that NK cell dysfunction is closely related to HCC progression. NK cells are the first-line effector cells of viral hepatitis and play a significant role by directly clearing virus-infected cells or by activating antigen-specific T cells by producing IFN-γ. In addition, chimeric antigen receptor (CAR) engineered NK cells suggest an exclusive opportunity to produce CAR-NKs with several specificities with fewer side effects. In the present review, we comprehensively discuss the innate immune landscape of the liver, particularly NK cells, and the impact of tumor immune microenvironment (TIME) on the function of NK cells and the biological function of HCC. Furthermore, the role of NK cells in HCC and HBV-induced HCC has also been comprehensively elaborated. We also elaborate on available NK cell-based immunotherapeutic approaches in HCC treatment and summarize current advancements in the treatment of HCC. This review will facilitate researchers to understand the importance of the innate immune landscape of NK cells and lead to devising innovative immunotherapeutic strategies for the systematic treatment of HCC.
