Abstract 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.
Wang et al. (Mon,) studied this question.