Beyond CAR-T Cells: exploring CAR-NK, CAR-M, and CAR-γδ T strategies in solid tumor immunotherapy

作者：Yingjie Hou, Shihua Hu, Liu Chong, Xin Chen, Yuru Wang, Yi Li, Zhiren Fu, Chunjing Feng, Yanhua Gong, Zichuan Liu, Shouchun Peng · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1675807 · 被引用次数：31 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、T-cell and B-cell Immunology

Adoptive cell therapy (ACT) employing chimeric antigen receptor (CAR) engineering represents a transformative advancement in cancer immunotherapy. CAR-T cell therapies have demonstrated significant clinical success in hematological malignancies, yet their application to solid tumors faces persistent challenges. Key limitations include the paucity of tumor-specific antigens, poor intratumoral infiltration, immunosuppressive tumor microenvironment (TME), and treatment-related toxicities such as cytokine release syndrome (CRS) and neurotoxicity. In contrast, CAR natural killer (CAR-NK) cells show promise in solid tumors such as ovarian, pancreatic, and glioblastoma, with encouraging preclinical and early clinical evidence, although limited persistence and antigen heterogeneity remain major challenges. Unlike CAR-T cells, CAR-NK therapies mediate tumor clearance through both cytotoxic (e.g., granzyme/perforin release) and cytokine-mediated mechanisms while mitigating toxicity risks. Their lack of human leukocyte antigen (HLA) dependency enables "off-the-shelf" manufacturing from allogeneic donors, circumventing patient-specific production bottlenecks. CAR-macrophage (CAR-M) therapies further address solid tumor barriers by leveraging innate phagocytic clearance, antigen-presenting functions, and TME penetration. Macrophages inherently infiltrate hypoxic tumor regions and remodel stromal barriers, enabling CAR-Ms to synergize with adaptive immunity by cross-priming T cells. Precli...