Emerging potential of CAR-NK cell therapy for hepatocellular carcinoma: current advances and translational challenges

Chimeric antigen receptor-natural killer (CAR-NK) therapy represents an emerging new direction in fighting against cancer. In recent years, it has attracted significant attention, largely due to its notable safety advantages over CAR-T cell therapy and its potential for reduced side effects. In this article, we will review the recent preclinical advances and translational challenges in CAR-NK therapy for the treatment of hepatocellular carcinoma (HCC). Several preclinical studies have successfully demonstrated that targeting HCC-associated tumor antigens such as glypican-3 and cluster of differentiation 147 (CD147) could exert a strong anti-tumor efficacy. However, only a few studies have entered the clinical stage, with none having progressed to late-phase trials. The clinical translation of CAR-NK in HCC is mainly hindered by significant challenges, including the immunosuppressive tumor microenvironment, inefficient tumor trafficking, tumor heterogeneity, and poor persistence of infused cells. To overcome these barriers, researchers have been exploring different innovative strategies such as disrupting the transforming growth factor-β signaling, engineering homing chemokine receptors, developing multi-specific CARs, and enhancing persistence with cytokine support (e.g., interleukin-15). Further ongoing research is important to optimize the CAR constructs and identify effective combination approaches to enhance the overall treatment efficacy.