br Glioblastoma GBM is the

Glioblastoma GBM is the highest-grade glioma (Grade IV) according to WHO classification and belongs to the most malignant form of 1661010 receptor tumor. It is an incurable disease despite the use of aggressive treatments that include surgery and radiotherapy, usually in combination with chemotherapy [13]. GBM utilizes several mechanisms to achieve fast growth and dissemination in the brain parenchyma, among them are rapid proliferation, invasion, the promotion of angiogenesis, and the induction of immunosuppression 14, 15. Gliomas actively recruit cells of the peripheral immune system by releasing several chemokines, such as CCL2 16, 17, 18, 19. Once within the tumor environment, immune cells are exposed to immunomodulatory cytokines and factors, such as TGF-β1 [20], resulting in the suppression of tumor-specific immunity. Thus, the recruitment of peripheral immune cells into the tumor suppresses tumor-specific immunity and promotes tumor growth. Myeloid cells, such as macrophages and microglia, infiltrate the GBM, to which they are attracted, at least partly, by the chemokine CCL2 18, 21, 22, 23. Myeloid cells comprise the predominant immune cell population in GBM tissue; indeed, their abundance correlates with the GBM grade 17, 20, 24. Notably, within the tumor microenvironment, macrophages acquire a tumorigenic anti-inflammatory phenotype 17, 25. As a result, these glioma-infiltrating macrophages support glioma invasion and angiogenesis, and suppress GBM-specific immunity 15, 24, 25. Other types of immune cell, such as T and B lymphocytes, natural killer (NK) cells, and dendritic cells (DCs), infiltrate gliomas to a lesser extent [26]. Some reports demonstrate that a higher degree of infiltration by CD8+ T cells in brain tumors is associated with less aggressive disease, while CD4+ regulatory T cells (Treg) infiltration is linked to poor outcome; however, the association of other immune cells with disease prognosis requires further investigation [27]. Finally, the molecular mechanisms regulating the immunosuppressive activities of immune cells in GBM and potential therapeutic targets to interfere with this process are mostly unknown. The malignancy of GBM results from its high proliferation rate, its ability to invade the surrounding brain parenchyma, and immunosuppression. These aspects of GBM malignancy are supported by the manipulation of several biological pathways to exploit not only intracellular tumor resources, but also the microenvironment provided by surrounding cells [28]. Augmented glycolysis or the Warburg effect 3, 28, 29 and abnormal tryptophan catabolism [30] are hallmarks of GBM. Specifically, Xiong and colleagues observed that a mutated form of a critical component of the TCA cycle, isocitrate dehydrogenase 1 (IDH1), is associated with HIF-1α-mediated carcinogenesis [29]. Their findings provide an important line of evidence that links metabolic dysfunction, through disruption of the IDH1 pathway and increases in HIF-1α activity, to increased transcriptional activity leading to more aggressive glioma growth. In addition, Michael Platten’s group reported that kynurenine (Kyn), an endogenous ligand for the transcription factor AHR derived from tryptophan, is produced by glioma cells [30]. The group suggested that the Kyn–AHR pathway contributes to GBM pathology by increasing the growth and motility of tumor cells and suppressing the immune response. Therefore, to understand the role of metabolism in GBM pathology, it is important to link specific metabolic signaling pathways to specific cell populations in the tumor microenvironment. Multiple lines of evidence indicate that the increase in aerobic glycolysis detected in GBM supports the elevated nutrient demands of fast-proliferating cancer cells by providing lipid and nucleotide biosynthesis [28]. In addition, this increased glycolysis has important effects on tumor-specific immunity and, consequently, tumor pathogenesis 31, 32. Indeed, the Warburg effect also promotes the production of lactate in anaerobic conditions, which attracts immune cells to the tumor microenvironment, where they are imprinted with a tumor-suppressing phenotype 33, 34, 35. For example, excessive accumulation of lactic acid in the tumor microenvironment can lead to disruption of the lactic acid gradient between the intracellular space of lymphoid cells and the extracellular milieu [21]. Through this mechanism, T cells can no longer export intracellular lactic acid efficiently, which leads to the disruption of metabolic processes and a consequent decrease in T cell function. Lactic acid can activate the IL-23/IL-17 pathway, which is a canonical proinflammatory pathway [21]. However, lactic acid acts on tumor-associated macrophages to polarize them toward an M2 state, augmenting tumor growth rates through a mechanism contingent on HIF-1α [33]. Therefore, lactic acid is an oncometabolite with important functions in cellular communication in the tumor microenvironment that can reprogram immune cells, such as T cells and macrophages, to become pathological tumor-assisting agents. Moreover, the tumor microenvironment activates HIF-1α and AHR signaling to promote the metabolic reprogramming of immune cells and further modulate antitumor immunity 29, 30. Thus, metabolic adaptation and the changes it imposes on the tumor microenvironment promote GBM survival and propagation by acting on both glioma and immune cells. Although several pathways contribute to GBM pathology, we focus here on the roles of HIF-1α and AHR signaling.