Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness

Simple Summary Given the rising mortality rate caused by GBM, current therapies do not appear to be effective in counteracting tumor progression. The role of adenosine and its interaction with specific receptor subtypes in various physiological functions has been studied for years. Only recently, adenosine has been defined as a tumor-protective target because of its accumulation in the tumor microenvironment. Current knowledge of the adenosine pathway and its involvement in brain tumors would support research in the development of adenosine receptor antagonists that could represent alternative treatments for glioblastoma, used either alone and/or in combination with chemotherapy, immunotherapy, or both. Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy.