CAR-NK cell(Shanghai Tongji Hospital)

CAR-based cell therapies have shown clinical success in treating various cancers, with CAR T cell therapies entering the clinical route and CAR NK cell therapies being evaluated in early-stage clinical trials. A key challenge is the presence of tumor-associated antigens on healthy cells, risking on-target off-tumor toxicities. Our comparative analysis of CAR T and CAR NK cells targeting the multiple myeloma-associated antigens BCMA, SLAMF7, and CD38 revealed that antigen density on target cells significantly modulates CAR NK cell activation and cytotoxicity. The cytotoxic potential of CAR NK cells was comparable to that of CAR T cells when targeting BCMA and CD38, but notable differences were observed in SLAMF7-directed CAR cells. While CAR sensitivity was similar in both cell types, CAR NK cell activity was balanced by inhibitory receptors like KIRs and NKG2A. This balance allows effective tumor control while potentially reducing on-target off-tumor effects on healthy cells with low antigen expression. Consequently, CAR NK cells offer greater flexibility in target antigen selection, potentially expanding the range of targetable antigens for cancer immunotherapy.

CAR-T cell therapy has shown promise but is constrained by side effects and limited efficacy in treating solid tumors. Compared to CAR-T cells, CAR natural killer (NK) cells derived from multiple versatile sources exhibit more favorable safety profiles and possess the unique ability to refine cytotoxic activity, serve as off-the-shelf options, and target a broad range of tumors. However, several challenges still impede the development and implementation of CAR NK cell therapy for solid tumors. This review article outlines the therapeutic strategies, advantages, limitations, and potential solutions, while providing insight into the future landscape by challenging current knowledge in the field. It also discusses optimizing CAR NK cell structure, addressing obstacles in the clinical utility of CAR NK cell therapy, and integrating it into standard cancer treatment regimens. Ultimately, we aim to navigate the crucial challenges in treating solid tumors and explore the future of this approach.