Adoptive macrophages reverse the immunosuppressive microenvironment in glioblastoma via programmed phenotypic polarization

Abstract Tumour-associated macrophages (TAMs) are abundant in glioblastoma (GBM) and play important roles in maintaining the suppressive tumour immune microenvironment (TIME). Strategies have been tried to deplete or transform the TAMs, but they face challenges to fundamentally reshape the TIME. Here, we report adoptively transferred macrophages as a new strategy to repolarize TAMs, modulate TIME and suppress GBM growth. We reveal adoptive macrophages primed to anti-inflammatory phenotype exhibit higher efficacy in traversing tumour vasculature and homing into GBM than those with pro-inflammatory phenotypes. Engineered anti-inflammatory macrophages, eM2-Mφs, are developed and show a unique characteristic of programmed phenotype repolarization. The adoptively transferred eM2-Mφs home to GBM efficiently post intravenous administration and their spontaneous transition into proinflammatory phenotype triggers reprogramming of endogenous TAMs. Moreover, low-dose irradiation (LDI) markedly enhances TAM infiltration and synergizes with adoptive eM2-Mφs to reverse the suppressive TIME. Combined treatment with LDI and eM2-Mφs followed by checkpoint inhibitor remarkably extends the survival of mouse models bearing intracranial GBM allografts. Collectively, this study provides an adoptive non-genetic engineered macrophage therapy to enhance immunotherapeutic response to GBM.