Next-generation CAR-NK cell therapy: engineering strategies, translational challenges, and future perspectives in cancer immunotherapy.

Natural killer (NK) cells play a central role in innate immune surveillance and represent a promising platform for next-generation cancer immunotherapy. Recent advances in chimeric antigen receptor (CAR) engineering have accelerated the development of CAR-NK cell therapies as potentially safer and more accessible alternatives to CAR-T cell therapy. Compared with CAR-T cells, CAR-NK therapies demonstrate lower risks of cytokine release syndrome and graft-versus-host disease while offering the potential for allogeneic "off-the-shelf" applications. Preclinical and early-phase clinical studies have shown encouraging antitumor activity of CAR-NK cells in both hematological malignancies and solid tumors. However, several translational challenges remain, including limited in vivo persistence, insufficient tumor trafficking, immunosuppressive tumor immune microenvironments, manufacturing variability, and restricted long-term clinical data. To overcome these barriers, emerging strategies such as CRISPR-based gene editing, cytokine-armored CAR constructs, multiplex engineering, checkpoint blockade combinations, and oncolytic virus-based approaches are being actively investigated. This review provides an updated overview of CAR-NK cell biology, engineering strategies, current clinical progress, major translational challenges, and future therapeutic opportunities. In addition, we discuss evolving combinatorial and next-generation engineering approaches that may improve persistence, safety, and therapeutic efficacy, ultimately facilitating the broader clinical translation of CAR-NK immunotherapy.