Role of the neurotransmitter-receptor pathway in T-cell tumor immunology and cancer immunotherapy

This review synthesizes how neurotransmitters—including glutamate, acetylcholine (ACh), γ-aminobutyric acid (GABA), serotonin (5-HT), and catecholamines—modulate T-cell immunity in the tumor microenvironment through activation, differentiation, trafficking, and checkpoint dependence. Glutamate amplifies T-cell receptor signaling but is counterbalanced by tumor-derived glutamate export. Cholinergic pathways exert dual effects through nicotinic and muscarinic receptors, whereas GABA generally imposes metabolic and signaling brakes that favor regulatory programs. Serotonin shows spatial divergence—suppressing peripheral responses but enhancing intratumoral cytotoxicity—and chronic β-adrenergic stress dampens effector function and limits immunotherapy efficacy. Advances in spatial multi-omics, single-cell profiling, and neuromodulation will help discover new targets across these axes. This review provides mechanistic insights and translational implications, highlighting emerging strategies such as glutamate receptor, metabotropic glutamate receptor 4 (mGluR4) or xCT (SLC7A11) inhibition, receptor subtype modulation, and β-blockade. Integrating neurotransmitter-receptor targeting with checkpoint inhibitors or cell therapies may improve the depth and durability of cancer immunotherapy.