CAR-macrophages: a new chapter in cancer immunotherapy

Chimeric antigen receptor T (CAR-T) cell therapy achieves remarkable success in hematological cancers, but its efficacy is severely limited in solid tumors by formidable obstacles including physical barriers, the highly immunosuppressive tumor microenvironment (TME), and antigen escape. To address these persistent challenges, chimeric antigen receptor-macrophage (CAR-M) therapy emerges as a promising alternative, leveraging intrinsic advantages of macrophages like unparalleled tumor infiltration, powerful phagocytosis, and high plasticity. The evolution of CAR-M is primarily defined by the intracellular signaling domain. CAR-M exerts its anti-tumor effects through multifaceted mechanisms, including direct enhanced phagocytosis and tumor cell killing, TME remodeling by repolarizing to a pro-inflammatory M1-like phenotype, releasing anti-tumor effectors, and degrading the extracellular matrix (ECM), and the activation of adaptive immunity <i>via</i> efficient antigen presentation. Despite its promise, CAR-M faces hurdles such as TME physical barriers and the potential for M2-like re-education. Current optimization strategies focus on enhancing tumor infiltration, overcoming immunosuppression with "armored" CAR-Ms, and improving safety with suicide switches. Encouraging pre-clinical data accelerates CAR-M into early-phase clinical trials for solid tumors, and the platform's utility is also being explored beyond oncology in infectious, autoimmune, and neurodegenerative diseases.