pH and Acidosis in Glioma and Brain Integrity: Review and Perspective

High-grade gliomas, particularly glioblastoma (GBM), constitute a class of primary brain tumors characterized by aggressive growth, diffuse infiltration, and poor prognosis. A hallmark of many solid tumors, including gliomas, is dysregulation of pH homeostasis, resulting in a reversed pH gradient whereby intracellular pH (pH i ) is maintained at near-normal to slightly alkaline levels, while extracellular pH (pH e ) becomes acidic. This acidosis is driven by metabolic reprogramming (aerobic glycolysis and elevated lactate/H + export), hypoxia, and inadequate clearance of acidic products. The acidic tumor microenvironment contributes to invasion, therapy resistance, immune suppression, blood–brain barrier disruption, and neuronal/vascular injury. The integrity of neural parenchyma, vasculature, and glial–vascular coupling is compromised in brain tumors. Herein the mechanisms of pH regulation in the brain and GBM, the sources and consequences of acidosis in GBM biology, the impact on brain tissue integrity, and therapeutic strategies targeting tumor acidosis are reviewed. We conclude by discussing future directions and the translational promise of pH-modulating interventions.