Interaction Between Lactic Acid and Gliomas in the Tumor Microenvironment: Potential Targets for Glioma Therapy.

Lactate is increasingly recognized as a central metabolic, epigenetic, and immunoregulatory determinant of glioma biology. In highly glycolytic gliomas, lactate dehydrogenase A (LDHA)-dependent lactate production and monocarboxylate transporter (MCT)-mediated transport support metabolic adaptation and multicellular metabolic crosstalk while contributing to extracellular acidification, immune suppression, and histone and non-histone lactylation. Recent studies have further uncovered subtype- and context-dependent mechanisms linking lactate to immune escape, nucleotide biosynthesis, cGAS-STING suppression, and resistance to temozolomide, radiotherapy, and anti-angiogenic therapy. Importantly, lactate biology differs substantially across molecular subtypes, particularly between isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant gliomas. Despite rapid mechanistic advances, clinical translation remains limited: MCT1 inhibition has reached early-phase clinical evaluation in advanced extracranial malignancies, whereas its relevance to glioma remains unestablished and selective LDHA-directed and lactylation-directed strategies remain predominantly preclinical. This review integrates lactate production and transport, immunometabolic regulation, lactylation, tumor-microenvironment remodeling, and emerging therapeutic strategies within a subtype-aware, mechanism-to-translation framework. We further critically evaluate evidence limitations, therapeutic maturity, metabolic compensation, biomarker requirements, and brain-delivery challenges to define priorities for precision lactate-targeted therapy in glioma.