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Published on: July 25, 2025
Human induced pluripotent stem cell-derived chimeric antigen receptor-macrophages eradicate IL-13Rα2-positive solid
Ying Yang1, Lujing Wang1, Yi Zhang1
1Institute of Pathology & Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing, PR China.
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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.
