Recent Progress in NKG2D CAR-NK Cells for Cancer Immunotherapy

Adoptive cellular therapy has emerged as one of the most pivotal modalities in cancer immunotherapy. Although chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in hematological malignancies, its broad application is hampered by severe immune-related toxicities, autologous manufacturing limitations, and suboptimal efficacy against most solid tumors, highlighting an urgent unmet clinical need for safer and more versatile cellular therapeutics. As a promising alternative, CAR-NK cell therapy exhibits inherent advantages in safety profile, off-the-shelf accessibility, and multimodal antitumor mechanisms. NKG2D, a pivotal activating receptor broadly expressed on NK cells, specifically recognizes stress-inducible ligands such as MICA/B and ULBP family molecules. These ligands are abundantly overexpressed in various hematological and solid malignancies yet rarely detected in normal tissues, thereby rendering NKG2D an ideal candidate for universal targeted immunotherapy. In this review, we systematically examine the structural design and iterative optimization of NKG2D CAR constructs and elucidate the inherent advantages of CAR-NK over conventional CAR-T cells. We also comprehensively review recent research advances in NKG2D CAR-NK across multiple malignancies, and critically analyze three pivotal translational bottlenecks, including tumor antigen escape, the immunosuppressive tumor microenvironment, and inadequate in vivo persistence. Moreover, we highlight current genetic engineering and combinatorial strategies to overcome these limitations, and outline future research directions focusing on the development of universal off-the-shelf products, multifunctional cell engineering, and rational combination regimens. By integrating mechanistic advances, preclinical findings and early clinical evidence, this review provides a systematic theoretical basis and translational guidance for the structural optimization, clinical translation, and widespread clinical adoption of NKG2D CAR-NK therapy, laying a solid foundation for its future development as a standardized universal anticancer cellular therapeutic.