Advancing CAR-NK cell therapy in solid tumors: Current landscape and future directions

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have emerged as a promising modern immunotherapeutic strategy, offering advantages over CAR-T cell therapy due to their innate cytotoxicity, safety profile, and potential for scalable, off-the-shelf allogeneic manufacturing. CAR-NK cells can be generated from multiple sources, with recent clinical studies demonstrating notable efficacy and lack of severe toxicity in hematologic malignancies. Nevertheless, the translation of this success to solid tumors is hampered by limited NK cell persistence, trafficking and infiltration challenges, and the hostile, immunosuppressive tumor microenvironment. This review provides a comprehensive synthesis of recent advances and innovations in CAR-NK cell engineering, addresses challenges posed by the solid tumor microenvironment, and highlights both rational preclinical strategies and early-phase clinical trials in solid tumors, underscoring the evolving and transformative promise of CAR-NK therapy for a broader range of human cancers in the near future.