Neurotransmitters, as crucial signaling molecules in the nervous system, have long been considered primarily responsible for information transmission between neurons [1], [2]. However, recent studies have revealed that classical neurotransmitters including glutamate, GABA, and dopamine, along with their receptors, are widely expressed in non-neuronal tissues and play pivotal roles in physiological processes such as immune regulation and metabolic control [3]. These groundbreaking discoveries have significantly expanded our understanding of the functional diversity of neurotransmitters, providing a novel theoretical foundation for comprehending the interactions between the nervous system and peripheral tissues. (Fig. 1, Fig. 2, Fig. 3)

Accumulating evidence has revealed the pivotal involvement of neurotransmitter systems in modulating the tumor microenvironment (TME) [4]. Extensive studies demonstrate that neoplastic cells and immune cells establish intricate communication networks via neurotransmitter-mediated pathways: (1) glutamate impairs CD8+ T cell effector functions through metabotropic glutamate receptor 4 (mGluR4) signaling [5]; (2) dopamine enhances natural killer (NK) cell cytotoxicity via dopamine D1-like receptor activation [6]; and (3) GABA facilitates the polarization of immunosuppressive M2-like tumor-associated macrophages (TAMs) through GABA-A receptors [7], among other mechanisms. These groundbreaking findings not only illuminate novel mechanisms of neurotransmitter-mediated tumor-immune regulation, but more importantly, provide a robust scientific foundation for developing targeted therapeutic interventions against neurotransmitter signaling networks.

Herein, this review will comprehensively synthesize cutting-edge advances in neurotransmitter research within tumor immunology and rigorously evaluate their clinical translational potential.