Beyond αβ T cells: unlocking the potential of diverse immune cells in CAR modification

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking advancement in cancer immunotherapy, demonstrating remarkable success in treating hematologic malignancies. However, its application in solid tumors remains challenging. The complex manufacturing process and severe treatmentrelated toxicities further limit its broader clinical application. To address these challenges, researchers are investigating alternative CAR-engineered immune cells, including CAR-NK cells, CAR-γδ T cells, and CARmacrophages (CAR-M), which offer distinct advantages over conventional CAR-T therapy. Notably, CAR-NK and CAR-γδ T cells exhibit HLA-independent cytotoxicity, making them promising ‘off-the-shelf’ therapeutic options. Meanwhile, CAR-M not only phagocytose tumor cells and present antigens but also remodel the immunosuppressive tumor microenvironment. Despite their potential, these innovative therapies still face several challenges in clinical application. This review systematically summarizes recent advances in CAR-T cells, CAR-NK cells, CAR-γδ T cells, and CAR-M for cancer treatment, providing a comprehensive analysis of their respective strengths, limitations, and future optimization strategies to support the clinical translation of next-generation CAR-based immunotherapies.