Human induced pluripotent stem cell‐derived chimeric antigen receptor‐macrophages eradicate <scp>IL</scp> ‐ <scp>13Rα2</scp> ‐positive solid tumors

Macrophages exhibit extensive tumor infiltration capacity across diverse solid malignancies, establishing macrophage-targeted immunotherapies as an emerging frontier in oncology. Genetic engineering of macrophages using chimeric antigen receptor (CAR) technology - enabling recognition and phagocytosis of neoplastic cells - is emerging as a potential therapeutic strategy against solid tumors. Human induced pluripotent stem cells (iPSCs) provide a renewable platform for the efficient differentiation of functionally competent macrophages. In this study, we engineered human iPSC-derived CAR macrophages (iCAR-M) targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2). Pan-tumor transcriptomic and immunohistochemical analyses revealed that IL-13Rα2, a tumor-associated antigen, was overexpressed in human glioblastoma (GBM), uterine carcinosarcoma (UCS), and melanoma specimens. In vitro phagocytosis assays revealed target-specific clearance of IL-13Rα2-positive tumor cells by iCAR-M. Intracranial administration of iCAR-M potently suppressed tumor growth, enhanced intratumoral cytotoxic T-cell infiltration, and prolonged the survival of humanized, immunocompetent mice bearing GBM xenografts. The administered iCAR-M maintained phagocytic capacity in vivo and acquired an M1-like pro-inflammatory phenotype. Comprehensive safety assessment revealed no detectable evidence of systemic toxicity or treatment-related neurotoxicity. Collectively, these results demonstrate the potent efficacy and favorable safety profile of iPSC-derived, IL-13Rα2-targeted CAR macrophages, supporting their therapeutic potential against solid tumors. © 2026 The Pathological Society of Great Britain and Ireland.