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CSF1R inhibitor C19 for glioma immunotherapy enabled by brain-targeting liposomal delivery

Wen-qin Song1,2, Yue-qian Wu2,3, Quan-feng Zhu4, Xing-ping Xia1,2, Rui Wang2, Lu Yang1,2, Li-hong Hu1, Jun-wei Wang1, Yong-zhuo Huang1,2,5, Hui-yuan Wang2
1 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
4 Shanghai Starriver Bilingual School, Shanghai 201108, China
5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
Correspondence to: Jun-wei Wang: jwwang@njucm.edu.cn, Yong-zhuo Huang: yzhuang@simm.ac.cn, Hui-yuan Wang: wanghuiyuan@simm.ac.cn,
DOI: 10.1038/s41401-025-01727-z
Received: 8 September 2025
Accepted: 30 November 2025
Advance online: 6 February 2026

Abstract

Immunotherapy targeting tumor-associated macrophages (TAMs) has emerged as a promising approach for treating glioma, driven by advances in drug discovery and development, including colony-stimulating factor 1 receptor (CSF1R) inhibitors. We previously developed a CSF1R inhibitor, C19, for TAM-targeting immunotherapy, which can reprogram TAMs and remodel the tumor immunosuppressive microenvironment. However, the application of CSF1R inhibitors in brain cancer is limited due to inefficient delivery across the blood–brain barrier (BBB). To address this limitation, we designed a brain-targeted liposomal delivery system (T12-Lipo) modified with the transferrin receptor-binding peptide T12. T12-Lipo can specifically bind to transferrin receptors, which are overexpressed in both the BBB and TAMs, thus enhancing the delivery efficiency of C19 across the BBB and to TAMs. This system promoted TAM repolarization toward an anti-tumor M1-like phenotype and thereby facilitated T-cell-mediated tumor killing. T12-Lipo improved the BBB permeability of C19, exhibiting significant therapeutic efficacy against glioma growth. The brain-targeted liposomal formulation of the CSF1R inhibitor C19 represents a promising and effective approach for glioma immunotherapy.
Keywords: glioma immunotherapy; tumor-associated macrophages; CSF1R inhibitor; blood–brain barrier; brain-targeted delivery

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