Lactate-Mediated Epigenetic and Immunometabolic Reprogramming in Glioma: An Emerging Axis Linking Metabolism to Tumor Progression

Background: Among primary malignant brain tumors in adults, glioblastoma is the most common and the most aggressive, characterized by profound metabolic reprogramming. This metabolic shift is essential for sustaining relentless proliferation and adapting to the challenging tumor microenvironment (TME). Central to this adaptation in glioma is the Warburg effect, which leads to excessive lactate production and accumulation, even in the presence of oxygen. This metabolic divergence significantly impacts the tumor immune microenvironment, promoting the recruitment of immunosuppressive cells and weakening the anti-tumor immune response. Core Content: This review provides a comprehensive analysis of the multifaceted roles of lactate in IDHwt glioma pathogenesis. It explores how lactate serves as a critical nexus connecting aberrant metabolism, epigenetic reprogramming (notably via histone lactylation), and immune evasion. The review delves into the molecular mechanisms by which lactate, particularly through the post-translational modification known as lactylation, directly modulates the epigenetic landscape to promote oncogene expression. Furthermore, it examines lactate’s role in acidifying the TME, promoting the immunosuppressive M2 polarization of glioma-associated macrophages (GAMs), and inhibiting the cytotoxic activity of T lymphocytes. Conclusions: This “lactate-centric” framework provides a unifying model that links metabolic dysregulation directly to malignant progression and therapeutic resistance (e.g., to TMZ). By elucidating this metabolic–epigenetic–immune axis, the review highlights a critical dependency that fuels glioma aggression. Finally, it discusses emerging therapeutic strategies aimed at targeting lactate production (LDHAi), transport (MCTi), and downstream epigenetic signaling (HDACi/p300i), offering novel avenues for integrative immunometabolic therapy.