CAR-Macrophage therapy for digestive system tumors: mechanisms, engineering and translational prospects

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable outcomes in the treatment of hematological malignancies, yet its efficacy is severely compromised in digestive system tumors. The inherent physical barriers and immunosuppressive tumor microenvironment (TME) of digestive tumors hinder the infiltration and effector function of antitumor immune cells, greatly limiting the efficacy of conventional immunotherapies and creating an urgent demand for novel targeted immunotherapeutic strategies. As pivotal resident immune cells in the TME, macrophages possess powerful phagocytic activity and antigen-presenting ability, making them ideal candidates for tumor immunotherapy. Chimeric antigen receptor macrophages (CAR-Ms) can penetrate and remodel the immunosuppressive TME and directly eliminate tumor cells, exhibiting unique advantages and great application potential for the treatment of digestive system tumors. Herein, we provide a comprehensive narrative review of the latest research advances in CAR-M therapy for digestive system tumors. This review mainly focuses on the cellular origins, innovative engineering and genetic modification strategies, and underlying antitumor mechanisms of CAR-Ms, as well as systematically discusses the current challenges and future prospects of CAR-M-based digestive tumor therapy. We aim to provide valuable theoretical references for the development and clinical translation of novel immunotherapies for digestive system tumors. With the rapid development of precision immunomedicine, CAR-M therapy is expected to become a promising alternative therapeutic strategy for clinical digestive system tumors treatment.