Radiation induces M2 polarization of glioma-associated macrophages via upregulation of glutamine synthetases.

Radiation-induced alterations in the tumor microenvironment (TME) may cause the shift of a few immune cells to immunosuppressive phenotypes, resulting in tumor radiotherapy resistance. The current study is aimed at investigating the impact of radiation on the polarization of glioma-associated macrophages (GAMs) and elucidating the underlying mechanisms. Through the irradiation (IR) of macrophages co-cultured with glioma cells and murine gliomas, we observed that IR promoted the polarization of GAMs towards a pro-tumorigenic M2 phenotype by modulating STAT5 to upregulate and activate glutamine synthetase (GS), consequently fostering glioma cells proliferation, migration, and invasion. Conversely, inhibition of GS activity with L-Methionine Sulfoximine (MSO) could shift macrophages towards the anti-tumor M1 phenotype. Moreover, in murine orthotopic glioma models, the combined treatment of MSO and radiation therapy exhibited a significant inhibitory effect on glioma growth. The combination also led to the suppression of tumor vasculature, increased infiltration of CD8+ T cells, and enhanced tumor cells apoptosis. In summary, our findings suggested that radiation combined with GS inhibition might potentially be a novel therapeutic strategy for glioma by modulating macrophage polarization and further promoting anti-tumor immunity.