Adenosine Signaling in Primary and Metastatic Brain Tumors: Immune Suppression, Tumor Progression, and Therapeutic...

Brain tumors, whether primary or metastatic, remain a significant cause of cancer-related mortality and are characterized by a profoundly immunosuppressive tumor microenvironment (TME). Among the signaling pathways that shape this environment, purinergic signaling-particularly the adenosine (ADO) axis-has emerged as a central regulator of tumor progression. In the TME, extracellular ATP (eATP) is sequentially converted into ADO by the ectonucleotidases CD39 and CD73, leading to sustained activation of adenosine P1 receptors. This review examines the receptor-specific roles of A1, A2A, A2B, and A3 receptors in modulating neuroinflammation, immune evasion, and therapeutic resistance across distinct brain tumor entities. At low extracellular ADO concentrations, high-affinity A1 and A2A receptors dominate signaling; A1 receptor (A1R) activation predominantly exerts neuroprotective effects by limiting glutamatergic excitotoxicity and preserving blood-brain barrier (BBB) integrity. However, under pathological conditions characterized by sustained ADO accumulation, this homeostatic balance is disrupted. Elevated ADO levels progressively engage low-affinity A2B and A3 receptors, while prolonged A2A receptor activation shifts from regulatory to immunosuppressive signaling, collectively driving T-cell dysfunction, angiogenesis, glioblastoma stem-like cell maintenance, and metastatic competence. Taken together, these findings highlight that pathological ADO receptor engagement in brain tumors is governed by extracellular ADO availability and receptor affinity, supporting a pharmacological framework in which selective inhibition of A2B and A3 receptors, combined with context-dependent modulation of A2A and preservation of A1R-mediated neuroprotective signaling, represents a rational strategy to limit tumor progression while minimizing adverse neurological effects.