Microglia in Glioblastomas: Molecular Insight and Immunotherapeutic Potential.

Simple Summary: Glioblastoma (GBM) is the most aggressive primary brain tumor. Despite intensive management with surgery, radio-, and chemotherapy, prognosis remains bleak, with a median survival of 15 months. Recently, microglia, the resident immune cells of the brain, have emerged as a potential therapeutic target for treatment of GBM. However, precisely how microglia interact with GBM cells and may be exploited for novel immunotherapies is not well understood. Here, we discuss the role of microglia in the GBM tumor microenvironment (TME), focusing particularly on the pro- and anti-tumorigenic pathways involved. We first introduce microglia and their role in the normal brain environment. Next, we discuss the microglia-GBM crosstalk, delving into specific factors that mediate these interactions. Finally, we present a comprehensive discussion of suitable microglial pathways that can be targeted to modulate the immune response in the TME to halt tumor progression. We discuss this in the context of current and past clinical trials targeting microglia, summarizing both successes and failures, and highlight promising pathways that are yet to be explored, suggesting future directions for study. Glioblastoma (GBM) is one of the most aggressive and devastating primary brain tumors, with a median survival of 15 months following diagnosis. Despite the intense treatment regimen which routinely includes maximal safe neurosurgical resection followed by adjuvant radio- and chemotherapy, the disease remains uniformly fatal. The poor prognosis associated with GBM is multifactorial owing to factors such as increased proliferation, angiogenesis, and metabolic switching to glycolytic pathways. Critically, GBM-mediated local and systemic immunosuppression result in inadequate immune surveillance and ultimately, tumor-immune escape. Microglia—the resident macrophages of the central nervous system (CNS)—play crucial roles in mediating the local immune response in the brain. Depending on the specific pathological cues, microglia are activated into either a pro-inflammatory, neurotoxic phenotype, known as M1, or an anti-inflammatory, regenerative phenotype, known as M2. In either case, microglia secrete corresponding pro- or anti-inflammatory cytokines and chemokines that either promote or hinder tumor growth. Herein, we review the interplay between GBM cells and resident microglia with a focus on contemporary studies highlighting the effect of GBM on the subtypes of microglia expressed, the associated cytokines/chemokines secreted, and ultimately, their impact on tumor pathogenesis. Finally, we explore how understanding the intricacies of the tumor-immune landscape can inform novel immunotherapeutic strategies against this devastating disease. [ABSTRACT FROM AUTHOR]