GMP-engineered CAR-myeloid cells: overcoming allogeneic barriers in CNS tumors

Abstract Chimeric antigen receptor (CAR)-T therapy is limited in solid tumors by poor infiltration and immunosuppression, while myeloid cell translation is hindered by expansion bottlenecks and allogeneic MHC mismatch. Now, Yue et al. establish an expandable granulocyte-monocyte progenitor (GMP) platform that overcomes three long-standing bottlenecks of macrophage-based therapy—poor ex vivo expansion, limited genetic tractability, and short-lived persistence after infusion. Critically, infused GMPs persist long-term in vivo, reconstitute functional myelopoiesis, and restore antibacterial immunity in chronic granulomatous disease (CGD) mice, demonstrating that GMP-derived macrophages are functionally competent. The authors also engineer a CAR-Fc construct that enables both direct phagocytosis and host Fc receptor-mediated trans -phagocytosis. In fully MHC-mismatched immunocompetent models, mature CAR-Fc macrophages mediate a "hit-and-run" effect—transient donor cell persistence coupled with durable host adaptive immunity. These findings redefine the feasibility of allogeneic myeloid cell therapy and provide a transformative roadmap for CAR-microglia against central nervous system (CNS) malignancies.