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  3. Adoptive macrophages suppress glioblastoma growth by reversing immunosuppressive microenvironment through programmed phenotype repolarization

Adoptive macrophages suppress glioblastoma growth by reversing immunosuppressive microenvironment through programmed phenotype repolarization

  • Cell Rep. 2025 Sep 26;44(10):116350. doi: 10.1016/j.celrep.2025.116350.
Yang Fan 1,  Hang Yin 2,  Jing Zhao 1,  Bolin Yao 1,  Guangli Cheng 1,  Yaqi Yang 3,  Minghao Yang 1,  Luo Chen 1,  Jian Chen 1,  Ji Zhou 1,  Ren Li 4,  Botao Zhao 4,  Xiao-Yong Zhang 4,  Cong Wang 5,  Xihui Gao 6,  Cong Li 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Immunoinflammatory Drug Innovation Center, Ministry of Education, State Key Laboratory of Medical Neurobiology, Shanghai 201203, China.
  • 2 School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Immunoinflammatory Drug Innovation Center, Ministry of Education, State Key Laboratory of Medical Neurobiology, Shanghai 201203, China; Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou 215123, China.
  • 3 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Science, Fudan University, Shanghai 200032, China.
  • 4 Institute of Science and Technology for Brain-inspired Intelligence, Fudan University, Shanghai 200433, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai 200433, China.
  • 5 School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Immunoinflammatory Drug Innovation Center, Ministry of Education, State Key Laboratory of Medical Neurobiology, Shanghai 201203, China. Electronic address: cong_wang@fudan.edu.cn.
  • 6 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Science, Fudan University, Shanghai 200032, China. Electronic address: gaoxihui@fudan.edu.cn.
  • 7 School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Immunoinflammatory Drug Innovation Center, Ministry of Education, State Key Laboratory of Medical Neurobiology, Shanghai 201203, China. Electronic address: congli@fudan.edu.cn.
PMID: 41014558 DOI: 10.1016/j.celrep.2025.116350
Abstract

Glioblastoma (GBM) is a highly lethal brain tumor resistant to immunotherapy due to poor brain drug delivery and an immunosuppressive microenvironment. This study introduces a macrophage-based adoptive cell therapy that reprograms the tumor immune landscape to suppress GBM growth. We reveal that macrophage homing to GBM is phenotype-dependent, with anti-inflammatory macrophages more efficiently navigating the brain vasculature and targeting tumors. Based on this observation, we developed engineered M2-like macrophages (eM2-Mφs) capable of programmable polarization. These adoptive cells maintain an anti-inflammatory phenotype during early circulation, allowing deep tumor infiltration, and subsequently switch to a proinflammatory state within the tumor to trigger immune activation. Treatment with eM2-Mφs alone, or combined with low-dose irradiation and/or checkpoint inhibitor, remarkably suppressed tumor growth and extended survival in mouse models. This approach offers a promising strategy to overcome GBM's immunosuppressive barriers and enhance immunotherapy efficacy.

Keywords

CP: Cancer; CP: Immunology; adoptive macrophage; glioblastoma; immunotherapy; phenotype polarization; tumor immune-microenvironment.

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