Chimeric Antigen Receptor Natural Killer T-Cell Therapy for Tumors: Promise and Progress

BACKGROUND: Therapy based on chimeric antigen receptor-engineered invariant natural killer T cells (chimeric antigen receptor natural killer T [CAR-NKT] cells) is an innovative cellular immunotherapy strategy that offers advantages over conventional CAR-T cell therapy in the treatment of solid tumors. SUMMARY: This article reviewed the research progress and current application of CAR-NKT cells in solid tumors. Current studies have shown that CAR-NKT cells can efficiently recognize tumor-associated antigens, infiltrate the tumor microenvironment, and exert antitumor effects through direct killing and cytokine secretion. Compared with CAR-T therapy, CAR-NKT therapy exhibits stronger antitumor potency and a reduced incidence of graft-versus-host disease. Furthermore, CAR-NKT cells can enhance antitumor immunity by regulating dendritic cells, NK cells, and CD8+ T cells. Early clinical trials for neuroblastoma and preclinical trials for other solid tumors have shown good safety and preliminary efficacy, and therapies have great potential for clinical translation. KEY MESSAGES: However, this therapy still faces challenges such as optimizing antigen selection, insufficient in vivo expansion and persistence, tumor heterogeneity, and immune suppression barriers. Future directions include advancing cytokine engineering and combination therapies. Collectively, CAR-NKT cells provide new ideas and new means to break through the difficulties in treating solid tumors and hold the promise of becoming the next generation of cellular immunotherapy.