Natural killer cell-based therapy for hepatocellular carcinoma (HCC): A literature review

Hepatocellular carcinoma (HCC) remains a significant global health threat characterized by aggressive progression and high mortality rates. Despite therapeutic advancements, survival for advanced stages is unacceptably low, necessitating innovative approaches like Natural Killer (NK) cell-based immunotherapy. NK cells are crucial innate immune components providing rapid tumor cytotoxicity without prior sensitization. However, the HCC tumor microenvironment (TME) presents a formidable barrier, inducing NK cell dysfunction through immunosuppressive cytokines like TGF-[Formula: see text], chronic hypoxia, and metabolic exhaustion driven by lipid accumulation. This literature review consolidates and integrates findings regarding current NK cell-based strategies in HCC, with particular emphasis on mechanisms of NK cell dysfunction within the TME and therapeutic approaches designed to restore their antitumor activity. Emerging therapeutic strategies involve cytokine-supported approaches, including the adoptive transfer of autologous or allogeneic NK cells expanded ex vivo using stimuli such as IL-15 and IL-21. In parallel, advances in genetic engineering have enabled the development of modified NK cells, including chimeric antigen receptor (CAR)-NK platforms targeting HCC-associated antigens such as glypican-3 (GPC3) and CD147 and bispecific and trispecific killer cell engagers (BiKEs and TriKEs). This review underscores the translational potential of NK cell-based therapies by highlighting unresolved knowledge gaps in the complex interplay between NK cells and the TME. These developments provide a foundation for optimizing NK cell immunotherapy and improving prognostic outcomes for patients with HCC.