CAR Macrophages in Brain Tumor Immunotherapy: Molecular Engineering Strategies and Emerging Frontiers

The CNS is partly shielded from immune attack, which allows tumor cells to escape many conventional therapies, including CAR-T. CAR-M therapy is an alternative approach that exploits the ability of myeloid cells to enter the CNS, engulf tumor cells, and shift the immunosuppressive microenvironment. This review focuses on molecular engineering principles for next-generation CAR-M constructs, including signaling domain selection, CD47-SIRPα checkpoint strategies, and gene delivery platforms for myeloid cells. We also discuss CNS-specific delivery routes and the multi-layered anti-tumor mechanisms of CAR-M, such as phagocytosis, TME remodeling, and innate–adaptive immune bridging. Combination strategies with checkpoint inhibitors, oncolytic viruses, and chemotherapy are analyzed, together with emerging approaches like SIGLEC9-based chimeric switch receptors, enucleated MSC-mediated in situ CAR-M generation, and circRNA-based CAR expression. We then address CNS-specific safety considerations and translational challenges.