CAR-M Therapy: From Concept to Clinical Translation in Solid Tumors.

While chimeric antigen receptor (CAR)-T-cell therapies have shown significant effectiveness in hematological malignancies, their efficacy in solid tumors remains limited by the hostile tumor microenvironment (TME) and antigen heterogeneity. Recently, CAR-Macrophage (CAR-M) therapy has emerged as a paradigm-shifting approach, leveraging the innate capability of macrophages to deeply infiltrate tumors and their plasticity to reverse immunosuppression. Unlike T cells, CAR-Ms not only mediate direct phagocytosis but also initiate epitope spreading, effectively bridging innate and adaptive immunity. This review critically examines the trajectory of CAR-M therapy from biological rationale to clinical reality. We dissect the engineering evolution of CAR constructs, arguing for macrophage-specific signaling domains (e.g., FcRγ, Megf10) over traditional T-cell designs. Crucially, we address the major bottlenecks in clinical translation, including the manufacturing challenges of non-expanding primary macrophages and the emerging shift toward induced pluripotent stem cell (iPSC)-derived platforms. Furthermore, we evaluate current clinical trial landscapes and discuss next-generation strategies such as in vivo programming via lipid nanoparticles (LNPs) and synthetic logic-gating to enhance safety. Ultimately, overcoming manufacturing constraints and optimizing delivery systems will be pivotal for CAR-M to evolve from a niche therapy into a standard-of-care modality for solid tumors.