Natural killer cell therapy in hepatocellular carcinoma: a comprehensive review

Hepatocellular carcinoma remains a major healthcare burden worldwide and is predicted to be the cause of death of 1.3 million people in 2040. Most HCC patients are diagnosed in advanced stages, leading to a poor prognosis. The development of targeted immunotherapies is essential to address this unmet clinical challenge. Natural killer (NK) cells have emerged as a promising cell-based therapeutic approach for treating solid tumors. NK cells have the distinctive ability to identify and destroy cancer cells without requiring prior sensitization. Here, we discuss potential approaches, developing strategies, and current challenges of NK cell therapy reported completely. In addition, advancements in immunotherapy, including adoptive NK cell therapy, and the strategies to boost NK cell function against HCC such as cytokine-based treatments, immune checkpoint inhibitors, vaccine-based approaches, genetic delivery, non-coding RNAs, antibody-based methods, and natural agents have been discussed. This comprehensive study provides a unique perspective by integrating recent findings on the differential impact of NK cells on HCC. We highlight the latest advances in NK cell engineering and immune checkpoint modulation, presenting a comparative analysis of therapeutic strategies. Furthermore, we critically assess the translational challenges associated with NK cell-based therapies, particularly focusing on their limited in vivo persistence and tumor immune evasion strategies.