CAR-Ms: Macrophage-Based Cellular Immunotherapies for Solid Tumors

Chimeric antigen receptor (CAR)-Ms represents an innovative frontier in cancer immunotherapy, offering solutions to the challenges associated with treating solid tumors. Unlike CAR-T cells, CAR-Ms exploit the natural tumor-infiltrating properties and adaptability of macrophages, enabling them to navigate the hostile TME and achieve targeted cytotoxic effects. This chapter explores the multifaceted role of macrophages in cancer, emphasizing their dual functionality as tumor-supporting or tumoricidal cells and how these properties are harnessed and reprogrammed for therapeutic purposes. The engineering of CAR-Ms involves the integration of tumor-specific antigen recognition domains, macrophage-optimized signaling domains, and prophagocytic enhancements, enabling these cells to directly kill tumor cells and remodel the TME. Early clinical studies with unmodified macrophages established the safety and feasibility of CAR-M-cell therapy, setting the stage for advanced CAR-M-cell technologies. Despite their potential, CAR-Ms face challenges such as efficient gene delivery, short macrophage lifespans, and maintaining functionality in the immunosuppressive TME. With promising preclinical data and ongoing clinical trials, CAR-Ms are poised to complement existing therapies, including checkpoint inhibitors and CAR-T cells, transforming the treatment landscape for solid tumors and offering new hope for patients with refractory cancers.