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

• Neurotransmitters such as glutamate, acetylcholine, GABA, serotonin, and catecholamines critically modulate T-cell functions in the tumor microenvironment, affecting activation, differentiation, trafficking, and checkpoint dependence. • Glutamate amplifies TCR signaling but tumor-derived glutamate export counterbalances this, while cholinergic pathways exert dual effects via nicotinic and muscarinic receptors, and GABA generally suppresses T-cell responses favoring regulatory programs. • Serotonin exhibits spatial divergence, suppressing peripheral responses but enhancing intratumoral cytotoxicity, and chronic β-adrenergic stress dampens effector function and limits immunotherapy efficacy. • Targeting neurotransmitter-receptor pathways, such as inhibiting glutamate receptors, mGluR4, or xCT, and using β-blockers, combined with checkpoint inhibitors or cell therapies, may improve the depth and durability of cancer immunotherapy.