Harnessing the Power of CAR-NK Cells for Solid Tumors: Challenges, Innovations, and Future Frontiers in Immunotherapy

Solid tumors remain a formidable challenge in cancer therapy, often evading even the most advanced immunotherapies. Natural killer (NK) cells, cytotoxic innate lymphocytes capable of recognizing and eliminating tumor cells without prior antigen sensitization, have emerged as a compelling alternative to T cells in adoptive cell therapy. Compared to chimeric antigen receptor (CAR)-T cells, CAR-engineered NK cells offer distinct advantages, including a substantially reduced risk of graft-versus-host disease (GvHD) and cytokine release syndrome (CRS). These features enable the development of "off-the-shelf" allogeneic cell products with improved safety and accessibility. Early clinical studies of CAR-NK cells have demonstrated encouraging efficacy in hematological malignancies alongside an excellent safety profile, fueling enthusiasm to extend this approach to solid tumors. However, the efficacy of CAR-NK cell therapy against solid tumors is limited by multiple barriers, including the immunosuppressive tumor microenvironment, poor infiltration, and persistence of NK cells in tumor tissues, heterogeneity of tumor antigen expression leading to immune escape, and the potential for NK cell dysfunction or exhaustion in chronic tumor settings. To overcome these obstacles, innovative engineering strategies are being developed. Approaches include armoring CAR-NK cells to resist tumor-induced immunosuppression, enhancing their trafficking and persistence, designing multi-antigen-targeted receptors, and incorporating built-in safety switches. This review highlights CAR-NK antitumor mechanisms, examines key challenges in solid tumor applications, and discusses cutting-edge advances and combination strategies aimed at unlocking the full therapeutic potential of CAR-NK cells. By addressing these challenges, CAR-NK cell therapy could open a new frontier in solid tumor immunotherapy.