Metabolic Reprogramming and Neurotransmitter Signaling Co-Option in the Glioma Immune Microenvironment: Dual-Axis Regulation of Immunosuppression.

Glioma, particularly glioblastoma (GBM), is characterized by a strongly immunosuppressive tumor microenvironment that limits durable therapeutic responses. This review examines two interacting regulatory aspects of this microenvironment: metabolic reprogramming and neurotransmitter signaling co-option. Metabolic reprogramming is characterized by Warburg-type aerobic glycolysis, lactate accumulation, nutrient competition, and epigenetic lactylation, which generate an acidic and metabolically restrictive niche that impairs cytotoxic immune populations. In parallel, neurotransmitter signaling co-option, particularly through glutamatergic and GABAergic pathways, can influence neuron-glioma communication, microglial/macrophage phenotypes, and selected lymphocyte functions. As direct evidence for bidirectional interactions between metabolic reprogramming and neurotransmitter signaling in glioma remains incomplete, this relationship is presented as a working neurometabolic framework rather than a fully resolved mechanism. Lactate-driven immunometabolic suppression and glutamatergic neuron-glioma signaling currently have the strongest support from glioma-specific studies, whereas some GABAergic, serotonergic, and macrophage-metabolic mechanisms remain emerging or context-dependent. The review also considers how mechanism-guided patient stratification, metabolically optimized immunotherapy and mechanism-based combination strategies targeting defined metabolic and neurotransmitter pathways may help restore antitumor immune competence within the glioma microenvironment.