Glioma-associated microglia and macrophages as a potential target for mTOR inhibition in glioblastoma

Introduction: Glioma-associated microglia/macrophages (GAM) constitute the predominant immune cell population in glioblastoma (GB). Both GB cells and GAM exhibit upregulated mTOR signaling. This study aimed to investigate the effects of pharmacological mTOR inhibition (mTORi) specifically on GAM.Materials and Methods: We conducted a comprehensive analysis of the GAM phenotype, including whole transcriptome analyses and cytokine profiling. Effects were investigated in a tumor cell/GAM co-culture model under mTORi with rapamycin or torin2 or under treatment with temozolomide, the standard chemotherapy agent for GB patients.Results: In our in vitro model, mTORi had significant effects on central biological functions of GAM, resulting in reduced proliferation and oxygen consumption. Additionally, treatment with mTORi induced a pro-inflammatory phenotype in microglial cells.Conclusions: Our findings demonstrate the profound relevance of mTOR signaling on GAM biology. Moreover, they provide rationales for therapeutic interventions targeting mTOR signaling specifically in GAM as a potential novel treatment strategy.