Chimeric antigen receptor-macrophages: A new paradigm for cell therapy.

Chimeric antigen receptor (CAR) technology has propelled CAR-T cells to transformative success in hematologic malignancies, yet translation to solid tumors remains limited, motivating exploration of alternative CAR-engineered immune effectors. Macrophages, sentinels of the innate immune system, are abundantly recruited to solid tumors, making them compelling candidates. Preclinical studies show that CAR-engineered macrophages (CAR-M) exhibit precise tumor homing, potent antigen-directed phagocytosis, and the capacity to remodel immunosuppressive tumor microenvironments (TMEs). Notably, early-phase clinical investigations indicate a favorable safety profile, strengthening confidence in their therapeutic potential against solid cancers. In this review, we synthesize design principles for CAR-M constructs, with a particular focus on emerging engineering strategies for next-generation CAR-M. We further discuss their applications in oncology and emerging non-oncologic indications, and summarize the current clinical trial landscape. We further propose a "4S framework" (specificity, switchability, synergy, and safety) to guide next-generation CAR-M development. Collectively, these advances support CAR-M as a new paradigm for cancer therapy and beyond.