Next-Generation CAR-Macrophage Therapies: Design Principles and Advances in Cancer Treatment.

Macrophages possess intrinsic tumor-homing and tissue-infiltrating abilities, performing various effector functions, including phagocytosis and antigen presentation. These properties make chimeric antigen receptor macrophages (CAR-M) a promising approach to overcoming major barriers in cellular therapy for solid tumors. This review systematically compares and critically evaluates key design variables that determine the therapeutic activity and clinical feasibility of CAR-M, including CAR architecture, macrophage source, gene-delivery method, and manufacturing strategy. We also discuss emerging engineering approaches tailored to macrophage biology, including macrophage-adapted intracellular signaling, regulation of phagocytic checkpoints, metabolic and phenotypic reprogramming, and combinations with immunomodulatory therapies. Their therapeutic potential and translational boundaries are assessed based on current preclinical evidence and early clinical findings. Notably, the major barriers to clinical translation are shifting from focusing solely on antitumor potency to addressing system-level challenges involving cell source and product consistency, in vivo expansion and persistence, phenotypic stability, off-target toxicity, and scalable manufacturing. Therefore, we propose that next-generation CAR-M development should move beyond conventional optimization of the CAR construct to multidimensional engineering centered on macrophage biology. Coordinated optimization of receptor signaling, antigen recognition, cell-state control, delivery, and safety mechanisms will be essential to balance efficacy, persistence, safety, and manufacturability. This review provides an integrated framework for the rational design and clinical evaluation of CAR-M and the development of next-generation CAR-M cellular therapy platforms.