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

作者：Yang Fan, Hang Yin, Jing Zhao, Bolin Yao, Guangli Cheng, Yaqi Yang, Minghao Yang, Luo Chen, Jian Chen, Ji Zhou, Li Ren, Botao Zhao, Xiao‐Yong Zhang, Cong Wang, Xihui Gao, Cong Li · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.116350 · 被引用次数：6 · 研究领域：Immune cells in cancer、Extracellular vesicles in disease、MicroRNA in disease regulation

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.