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

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.