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

Abstract

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.

1. Introduction

T cells are central effectors of the adaptive immune system and are essential for maintaining immune homeostasis and orchestrating antitumor immune responses [1,2]. T cells are broadly classified into cytotoxic T lymphocytes (CD8+ T cells), which eliminate cancer cells primarily through perforin- and granzyme-mediated killing, and helper T cells (CD4+ T cells), which secrete cytokines to shape the immune microenvironment, promote immune-cell activation, and sustain antigen-specific responses [3–5]. Studies in tumor immunology have shown that T cells play a pivotal role in recognizing and clearing malignant cells, whereas cancer cells evade immune elimination by upregulating immune checkpoints, secreting immunosuppressive factors, and recruiting regulatory T cells (Tregs) [6,7].

Neurotransmitters are chemical signaling molecules released by neurons and other cell types. They include classical small-molecule transmitters—such as acetylcholine, γ-aminobutyric acid, and glutamate—and monoamines (e.g., dopamine and 5-hydroxytryptamine/serotonin), as well as peptide transmitters. Their functions extend beyond synaptic signaling within the nervous system to important roles in immune regulation [8–10]. Growing evidence indicates that immune cells, including T cells, also express neurotransmitters and their receptors and can modulate their proliferation, differentiation, and effector functions through these pathways. This phenomenon underpins a fundamental axis of neuro-immune crosstalk [11,12]. There are bidirectional signaling pathways between the nervous system and immune system: the nervous system modulates peripheral inflammation and immune responses via the vagus nerve, the sympathetic nervous system, and associated neurotransmitters, whereas the immune system can influence central nervous system activity through cytokines and other mediators [13–15]. Within the tumor microenvironment, nerve fibers can innervate tumor tissue and release specific neurotransmitters that shape immune-cell function and may directly promote tumor-cell proliferation and metastasis [16–18]. For example, norepinephrine released by sympathetic nerves can suppress the antitumor activity of CD8+ T cells via β-adrenergic receptors, thereby accelerating tumor progression [19]. Accordingly, interrogating the “neurotransmitter-receptor-T-cell” axis to elucidate neuro-immune-tumor interactions not only reveals new routes of immune evasion but also identifies potential intervention targets for cancer immunotherapy. This review synthesizes current advances, summarizes the mechanisms by which neurotransmitter–receptor signaling shapes T-cell–mediated tumor immunity and cancer immunotherapy, and discusses prospects for translational application (Figure 1).