Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness

Abstract

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.

Engineering the glioblastoma microenvironment with bioactive nanoparticles for effective immunotherapy

“…Adenosine, a potent immunosuppressant produced in large quantities in hypoxic conditions by GBM cells and exported into the extracellular space, increases cancer aggressiveness and dampens the immune response through A2A receptors (A2AR) on immune cells. [77][78][79] Arginine promotes tumorigenesis and angiogenesis 80 and is provided by external sources since the urea cycle, the primary source of arginine, is inhibited in GBM cells through the silencing of argininosuccinate synthetase 1. 81 2.3.2 Immune cell metabolism.…”