Potential of CAR-Macrophages Derived from Induced Pluripotent Stem Cells (iMacs) for Solid Tumor Therapy.

Macrophages, a type of immune cell, perform essential functions in the immune system, including controlling inflammation, facilitating tissue healing, and defending the body against disease. However, in solid tumors, they are often reprogrammed into tumor-associated macrophages (TAMs) that support tumors through promotion of blood vessel growth, suppressing immune responses, and promoting tumor spread. Macrophages derived from blood-based sources, including monocytes and peripheral blood mononuclear cells (PBMCs), suffer from three major limitations: inconsistency across different donors, limited survival outside the body, and technical challenges in genetic modification. Consequently, this hinders their research and therapeutic use. Induced Pluripotent Stem Cell-derived macrophages (iMacs) address these issues by providing a renewable and scalable cell source that is genetically flexible while maintaining the natural functions of macrophages. This has opened the possibility for developing chimeric antigen receptor (CAR)-modified iMacs, which combine the ability of macrophages to engulf and destroy cells with precise tumor targeting capabilities. These modified cells can reshape the tumor microenvironment (TME), trigger the body’s targeted immune response, and enhance anti-tumor activity. Evidence from preclinical models demonstrate antigen-dependent anti-tumor activity and immune activation. Initial clinical studies indicate acceptable safety profiles and tumor infiltration in patients with advanced solid tumors. This review explores the recent progress in developing these iMacs therapies against solid tumors and their potential, as well as major biological, safety, and manufacturing challenges to be addressed for clinical use. Addressing these challenges through standardized production methods and combination with existing cancer drugs could establish iMacs as a viable treatment platform for solid tumors.