Advances in the study of the relationship between neurotransmitters and gastric cancer

Abstract

Emerging evidence underscores the critical, yet frequently underrecognized, role of the nervous system in the development and progression of gastric cancer (GC), primarily mediated through complex neuro-tumoral interactions and modulation of immune responses. GC cells actively invade neural structures, inducing aberrant nerve growth, while, in parallel, neural components infiltrate the tumor microenvironment, collectively promoting tumor proliferation, dissemination, and resistance to therapy. These bidirectional processes are regulated by diverse neurotransmitter systems—including monoaminergic, cholinergic, amino acid-based, peptidergic, and purinergic pathways—which are aberrantly produced by both neurons and malignant cells. Beyond their canonical function in neural signaling, these neuromediators exert diverse effects on tumor biology, coordinating multiple facets of GC progression, including invasion, metastasis, and cellular expansion. This review synthesizes current advances and outlines future directions in elucidating the mechanistic contributions of neurotransmitters to GC pathophysiology.

Key Words: Neurotransmitters; Gastric cancer; Signaling pathway transmission; Neuro-immune regulation; Tumor microenvironment

Core Tip: The nervous system plays a critical but underrecognized role in gastric cancer (GC) progression through bidirectional neuro-tumoral interactions. Neurotransmitters—including norepinephrine, acetylcholine, glutamate, γ-aminobutyric acid, adenosine, and neuropeptide Y—produced by both neurons and malignant cells, actively reprogram the tumor microenvironment. These mediators regulate proliferation, invasion, metastasis, immune evasion, and therapeutic resistance in GC. This review highlights advances in understanding neurotransmitter-driven mechanisms and introduces the concept of “neuro-gastric oncology”, providing a rationale for novel therapeutic strategies targeting neuro-tumoral signaling pathways.

INTRODUCTION

Gastric cancer (GC) is the fifth leading cause of cancer-related mortality worldwide, with over one million new diagnoses annually. Approximately 320000 of these cases occur each year in China[1,2]. A downward pattern has been observed in the population attributable fraction (PAF) for Helicobacter pylori (H. pylori) infection, cigarette smoking, intake of pickled vegetables, and alcohol use, whereas the PAF associated with excess body mass index and diabetes has continued to rise. Nevertheless, H. pylori infection is expected to remain the predominant determinant of GC risk in China for the foreseeable future[2]. The tumor microenvironment (TME) in GC is densely innervated, and neurotransmitters—once considered exclusive to neural communication—have emerged as pivotal regulators of malignant phenotypes[3]. Mounting data indicate that these signaling molecules, produced by both neuronal and tumor cells, actively influence GC progression through dynamic reprogramming of the TME[4-6].

Aberrant neurotransmitter expression patterns within GC have been shown to activate diverse intracellular signaling pathways, thereby contributing to tumor initiation and progression. For example, norepinephrine (NE) signal through β2-adrenergic receptors, facilitating metastasis via MMP-7/STAT3 activation and concurrently suppressing CD8⁺ cytotoxic T-cell responses[7-9]. Acetylcholine (Ach) engages M3 muscarinic and α7 nicotinic receptors, promoting cancer stemness via the Wnt/YAP axis and conferring chemoresistance through PI3K/AKT signaling[10,11]. Dysregulation of excitatory and inhibitory neurotransmitters—including glutamate and γ-aminobutyric acid (GABA)—alters tumor metabolic programs[12,13], while adenosine (ADO), via the CD73/A2AR axis[14], and neuropeptide Y (NPY), through Y1 receptor signaling, contribute to immunosuppressive niche formation[15] (Table 1).

Table 1 The function of neurotransmitters in gastric cancer.

Neurotransmitter	Receptor	Effects on gastric cancer
NE/E	β2-AR[6,8,9,11,23,26-30]	Promote proliferation, migration, invasion, EMT, metastasis, angiogenesis, DNA damage; inhibit immunosuppressive TME
DA	D2R[31,32,39,41,42]	Inhibit growth, invasion, metastasis, angiogenesis; promote antitumor immunity
5-HT	HTR2B[52-55]	Promote tumor occurrence, growth; inhibit ferroptosis and immunosuppressive TME
	HTR1D[56]	Promote proliferation and migration
ACh	M3[62,66,69-71]	Promote proliferation, tumor growth, and NGF expression
	α5-nAChR[76-78]	Promote proliferation, EMT; inhibit apoptosis
	α7-nAChR[79-82,85-91]	Promote proliferation, invasion, migration, angiogenesis, antitumor immunity; inhibit chemotherapy efficacy
GABA	GABA-A[102-104,106]	Promote proliferation, tumor growth; immune escape
	GABRD[105,107]	Promote proliferation, invasion; inhibit apoptosis
Glu	GRIK 2[110]	Inhibit tumor growth and migration
Gastrin	CCK2R[122-126]	Promote proliferation, invasion, migration, angiogenesis; inhibit apoptosis
CCK	CCK2R[124,130]	Promote proliferation, tumor growth
SST	SSTR1[134]	Inhibit proliferation, invasion, migration
	SSTR3[133]	Inhibit proliferation and apoptosis
SP	NK1R[119,143,144]	Promote proliferation, invasion, migration, adhesion
NPY	Y1R[15,153]	Promote proliferation, migration, angiogenesis
	Y2R[120,154]	Promote proliferation and angiogenesis
ADO	A2B[156]	Promote EMT and migration
	A2A[14,158]	Promote tumor escape
ATP	P2X7R[155,159-161]	Promote tumor occurrence, proliferation, EMT, invasion, migration

NE: Norepinephrine; E: Epinephrine; EMT: Epithelial-mesenchymal transition; TME: Tumor microenvironment; DA: Dopamine; 5-HT: Serotonin; Ach: Acetylcholine; GABA: Γ-aminobutyric acid; Glu: Glutamate; CCK: Cholecystokinin; SST: Somatostatin; SP: Substance P; NPY: Neuropeptide Y; ADO: Adenosine.

This review integrates current findings on the role of distinct neurotransmitter classes in GC, emphasizing their effects on the TME and outlining potential therapeutic implications. Collectively, these insights lay the groundwork for a conceptual framework of “neuro-gastric oncology”, providing a rationale for developing targeted interventions that disrupt neurotransmitter-driven tumor mechanisms (Figure 1).

Figure 1 Introduction figure of the “neurotransmitters-immunity-tumors” axis. Monoamines, cholinergic agents, amino acid derivatives, peptides, and purinergic neurotransmitters within the nervous system exert bidirectional effects on gastric carcinoma. Certain neurotransmitters promote cellular proliferation, invasive behavior, and metastatic progression, thereby facilitating tumor advancement. In contrast, others suppress oncogenic activity and restrain tumor growth. Moreover, neurotransmitters regulate the function of immune effector and suppressor cells, which dynamically interact with gastric cancer cells. The coordinated regulation of neurotransmitters, immune components, and malignant cells constitutes the so-called “neurotransmitter-immune-tumor” axis (by figdraw.com, Supplementary material).

LITERATURE SEARCH STRATEGY

A comprehensive literature search was conducted using PubMed, Web of Science, and Google Scholar databases. Keywords included: "Neurotransmitter”, "gastric cancer”, "neuro-immune axis”, "monoamine”, "acetylcholine”, "GABA”, "glutamate”, "neuropeptide”, "purinergic signaling”, and specific receptor names (e.g., "β2-adrenergic receptor”, "M3 muscarinic receptor"). Articles published between 2000 and 2025 were included, with emphasis on original research, meta-analyses, and high-impact reviews. Studies were selected based on relevance to neurotransmitter mechanisms in GC, including in vitro, in vivo, and clinical evidence. Although this review emphasizes GC, relevant findings on neurotransmitters in other gastrointestinal malignancies (e.g., colorectal, pancreatic) may also provide insights and will be briefly discussed.

MONOAMINE NEUROTRANSMITTERS

Monoamine neurotransmitters constitute a predominant class of signaling molecules in the nervous system, including epinephrine (E), NE, dopamine (DA), and serotonin (5-HT). Studies have shown that neurotransmitters such as NE are abundantly released through activation of the hypothalamic-pituitary-adrenal (HPA) axis by the sympathetic nervous system in response to stress[16]. Notably, increasing evidence suggests that stress responses critically enhance tumor cell proliferation and migration[17]. From the standpoint of pathophysiology, stress can manifest as either acute or chronic, with the latter being more consistently implicated in the initiation and progression of malignancies in experimental models[18]. Sustained stress exposure results in persistent secretion of catecholamines, which, as demonstrated in both in vitro and in vivo studies, modulate GC cell behavior by driving oncogenic traits such as uncontrolled growth, enhanced invasiveness, and metastatic spread[19,20]. Although these observations delineate critical mechanistic connections, the majority of supporting evidence derives from preclinical research, leaving their clinical relevance incompletely clarified. Within this context, the present section examines the potential roles of principal monoamine neurotransmitters in shaping the biological characteristics of GC cells.

E/NE and GC

E and NE primarily function within the sympathetic nervous system by engaging two receptor types: ADRA and ADRB receptors. Notably, research has indicated that in GC progression, these catecholamines predominantly interact with β2-adrenergic receptors, initiating downstream signaling cascades[7]. From a metastasis perspective, catecholamines have been shown to enhance the expression of premetastatic matrix metalloproteinases (MMPs) in tumor cells[21]. Specifically, STAT3 and c-Jun, activated by catecholamines, bind to the AP-1 binding site (-67 to -61) on the MMP-7 promoter, leading to transactivation of MMP-7 and facilitating tumor dissemination[8]. GC cells exhibit responsiveness to NE and catecholamines, triggering β2-AR/PKA/YKL-40 signaling, which promotes cellular proliferation, migration, and invasion, ultimately driving metastasis[6]. Intriguingly, depression has been linked to increased GC invasiveness and metastatic potential through neuroendocrine-induced activation of the β2-AR/MACC1 signaling axis[22]. From an angiogenesis standpoint, β-adrenergic receptor stimulation modulates VEGF gene expression via the PKA pathway, leading to elevated VEGF production and enhanced tumor angiogenesis[23]. Downstream effectors of ADRB signaling, such as CREB, have been implicated in mediating stress hormone-induced tumor proliferation, migration, and angiogenesis while concurrently suppressing apoptosis in preclinical models[24,25]. Moreover, β-adrenergic receptor signaling through Gs-PKA and β-inhibin pathways contributes to genomic instability by promoting DNA damage accumulation and suppressing p53 expression[26]. Lu et al[27] demonstrated that exposure of GC cells to the β2-AR agonist isoproterenol initiates epithelial-mesenchymal transition (EMT) via downregulation of epithelial markers (E-cadherin and β-catenin) and upregulation of mesenchymal proteins, including α-SMA, vimentin, and snail. This finding was corroborated by Wei et al[28], although this evidence remains restricted to in vitro systems. NE inhibits CD8⁺ T cell function via β2-AR and activates tumor-associated macrophages (TAMs) to secrete immunosuppressive factors (e.g., PD-L1), resulting in an immunosuppressive TME to promote GC progression[9]. Furthermore, emerging studies suggest that NE enhances tumor cell glycolysis, implying that malignancies exhibiting metabolic dysregulation alongside high catecholamine levels may be particularly responsive to metabolic-targeted or immunotherapeutic interventions[29]. Importantly, β2-AR antagonists such as ICI 118551 have been shown to reverse some of these effects in model systems, and early studies combining β-blockers with immune checkpoint inhibitors have demonstrated synergistic efficacy in animals[30]. However, translation into clinical benefit remains to be established, and current data should be interpreted cautiously.

DA and GC

DA, a key neurotransmitter in the gastrointestinal tract, plays diverse physiological roles in intestinal function. Research has demonstrated that DA can suppress tumor cell proliferation, invasion, growth, and angiogenesis[31,32]. Its effects in GC cells are mediated through DA receptors (DRs), which are categorized into five subtypes (D1R-D5R) that are widely distributed in the gastrointestinal system[33]. These receptors are further classified into two families: D1-like (D1, D5), which stimulate adenylyl cyclase to elevate intracellular cAMP, and D2-like (D2, D3, D4), which reduce cAMP levels and regulate Ca²⁺ as well as phospholipase C signaling pathways[34,35]. Among them, D2R has been implicated in suppressing IGF-I-driven proliferation of GC cells in preclinical models[32]. DA exerts its inhibitory effects on invasion, migration, and MMP-13 production by acting through D2R to suppress EGFR and AKT activation[36]. Conversely, overexpression of DA- and cAMP-regulated phosphoprotein DARPP-32 has been identified as an early molecular event in gastric tumorigenesis. Preclinical data suggest that DARPP-32 can activate the IGF1R/SRC/STAT3 axis, thereby supporting tumor initiation[37,38]. As discussed earlier, NE and E enhance VEGF expression, thereby promoting tumor angiogenesis. In contrast, DA does not upregulate proangiogenic molecules such as VPF/VEGF but instead downregulates VEGFR-2-mediated signaling in tumor endothelial cells and endothelial progenitor cells via D2R[39,40]. Studies indicate that at specific concentrations, DA enhances antitumor immunity in vivo by activating effector T cells (Teffs) while suppressing regulatory T cells (Tregs). By contrast, in cancer patients, markedly elevated circulating DA can compromise Teff proliferation and cytotoxic function through receptors such as D1R, and may also induce lymphocyte apoptosis via oxidative stress, ultimately resulting in immunosuppression. Moreover, DA promotes the polarization of TAMs toward an M1-like phenotype through D2R signaling, highlighting its paradoxical function as both an enhancer and suppressor of immune responses within the TME[41,42]. Interestingly, a study by Liu et al[43] revealed that DA transporter gene (SLC6A3) expression was markedly elevated in GC tissues but significantly reduced following surgical resection. This suggests that SLC6A3, as a DA transporter, may modulate GC progression by influencing DA-associated genes. Additionally, the DR antagonist ONC201, evaluated in preclinical and early translational studies in pancreatic cancer, has shown promise in combination therapies[44]. Nevertheless, direct clinical evidence in GC is currently lacking, and the therapeutic potential of targeting DA pathways requires rigorous clinical validation.

5-HT and GC

5-HT, a biogenic amine derived from tryptophan, is a well-established neurotransmitter in the central nervous system. It plays a crucial role in modulating gastrointestinal motility, vasodilation, and secretion[45,46]. The 5-HT system is regulated by seven receptor families (5-HTR1-5-HTR7) and 17 subtypes (HTR1A-F, 2A-C, 3A-E, 4, 5A, 6, and 7), which include both G protein-coupled receptors and ion channels[45,47]. Within the gastrointestinal tract, smooth muscle, enteric neurons, epithelial cells, and immune cells predominantly express 5-HTR1-4, and 5-HTR7[48]. Notably, approximately 90% of 5-HT is synthesized and localized within enterochromaffin cells[49]. Preclinical evidence suggests that dysregulated 5-HT signaling may contribute to tumorigenesis. Several receptor antagonists, including ondansetron, sertraline, and fluoxetine, have demonstrated tumor-suppressive effects in cell and animal models[50-52]. Recent findings suggest that abnormal overexpression of the 5-HTR2B subtype contributes to tumorigenesis. HTR2B plays a pivotal role in promoting GC cell survival by modulating the PI3K signaling cascade. Additionally, its activation enhances HIF1α and ABCD1 expression while reducing lipid peroxidation and ferroptosis. This study further elucidated the correlation between HTR2B receptor expression and clinical prognosis in GC patients[53]. Previous reports have indicated that the HTR2B and 5-HTR7 signaling pathways promote the development of anti-inflammatory M2 macrophages, while the latter promotes tumor development. Abnormal 5-HT signaling can promote tumor growth and contribute to the formation of an immunosuppressive TME that supports tumor survival[54,55]. In addition, expression of 5-HTR1D has been associated with proliferation marker Ki-67 in GC specimens. Inhibition of 5-HTR1D, either pharmacologically or genetically, reduced proliferation and migration in vitro and impaired cell cycle progression[56]. These findings suggest potential prognostic and therapeutic relevance, but they remain largely restricted to preclinical studies. While this evidence highlights a potential connection between 5-HT receptor expression and GC prognosis, the underlying mechanisms remain insufficiently explored. Clinical evidence is still emerging, and most data are derived from preclinical models. Further human studies are needed to validate these mechanisms. Further human studies are essential to establish the clinical significance of these pathways and to determine whether serotonergic modulation could represent a viable therapeutic strategy.

CHOLINERGIC NEUROTRANSMITTERS

ACh serves as a crucial neurotransmitter within both central and peripheral nervous systems, where it plays essential roles in gastric physiology. Its primary functions in the stomach include stimulating gastric acid secretion, enhancing gastric motility to facilitate emptying, and inducing the release of pepsinogen from chief cells in the gastric mucosa, thereby aiding digestion[57-59]. Beyond its physiological roles, ACh is implicated in the pathogenesis of various gastric disorders, including gastroesophageal reflux disease, peptic ulcer disease, and GC[60-62]. Emerging evidence indicates that ACh contributes to GC progression by promoting proliferation and inhibiting apoptosis, primarily through the upregulation of muscarinic M3 receptors and choline acetyltransferase (ChAT), a key enzyme in ACh biosynthesis[63]. Given its involvement in tumorigenesis, this review aims to further explore the influence of ACh on GC through distinct muscarinic and nicotinic ACh receptor subtypes.

Muscarinic ACh receptors and GC

Muscarinic receptors, classified as class A (rhodopsin-like) GPCRs, are distinct from nicotinic receptors due to their preferential affinity for muscarine over nicotine[64]. Five principal subtypes (M1-M5), encoded by CHRM1-CHRM5, mediate various parasympathetic functions, with the M3 receptor being the most abundantly expressed subtype in the gastrointestinal tract[65]. GC cells autonomously produce and secrete ACh, which activates M3 receptors in both autocrine and paracrine manners, triggering EGFR transactivation and facilitating tumor cell proliferation. Compared with normal gastric epithelial cells, GC cell lines exhibit elevated expression of ChAT, further amplifying autocrine and paracrine ACh signaling via M3R and EGFR pathways to promote tumorigenesis[62,63]. Preclinical studies have implicated M3R in driving proliferation through EGFR/AKT activation[66], and inhibition with antagonists such as 4-DAMP or Tuffina reduced proliferation, sensitized cells to 5-fluorouracil (5-FU), and promoted apoptosis[62,67]. Recent investigations have explored the involvement of the cholinergic system in tumor cell proliferation and oncogenesis. Studies utilizing Dclk-positive cluster cells revealed that cholinergic stimulation in the gastric epithelium induces NGF expression, which subsequently fosters tumor development. This suggests a positive feedback loop where NGF secretion further enhances cholinergic nerve expansion[68]. The vagus nerve has also been identified as a critical modulator of Wnt signaling in gastric tumorigenesis, a pathway essential for epithelial homeostasis in the stomach and intestine and implicated in certain GC subtypes[69,70]. Recent findings indicate that ACh enhances LGR5⁺ stem cell proliferation and tumor growth through Hippo-YAP-mediated regulation of Wnt signaling[71,72]. Knockdown of M3R in animal models suppressed Wnt signaling and tumor progression, while increased intratumoral innervation correlated with disease severity[69]. Beyond GC, studies in colorectal cancer cells showed that muscarinic blockade reduced PD-L1/PD-L2 expression and limited immune evasion[73]. These data suggest that cholinergic signaling may influence both tumor-intrinsic growth and immune modulation. However, much of the current evidence is derived from preclinical systems, and whether muscarinic signaling represents a clinically actionable target in GC remains uncertain.

Nicotinic ACh receptors and GC

A substantial body of research indicates that nAChRs serve as key mediators of nicotine’s effects on GC. Compared to normal gastric epithelial cells, GC cells exhibit an increased number and density of β-subunit-containing nAChRs[74]. Early investigations have linked prolonged nicotine exposure to a higher incidence of gastric malignancies[75]. Although current knowledge regarding nAChR-mediated signaling in GC remains limited, two subtypes, α5 and α7, have been extensively examined. Elevated α5-nAChR expression has been reported in gastric tumor specimens, and preclinical studies suggest that its activation promotes proliferation and resistance to cisplatin via AKT signaling, accompanied by upregulation of anti-apoptotic proteins such as Survivin and Bcl-2[76,77]. Nicotine has also been shown to activate ERK/5-LOX signaling, thereby enhancing proliferation, EMT, and invasion in cell-based models[78]. The α7 subtype exhibits a broader expression profile. Nicotine and tobacco-derived nitrosamines (NNK, NNN, DEN) bind strongly to α7-nAChR, initiating downstream signaling linked to tumor growth and invasion[79-81]. α7-nAChR is expressed in macrophages and T cells and is involved in the regulation of immune function and inflammatory response. α7-nAChR activation promotes enhanced Treg cell function and M2-type macrophage polarization, thereby suppressing anti-tumor immunity[82]. Wang et al's research[83] demonstrated that NNK significantly enhances the migratory capacity of human gastric adenocarcinoma cells (AGS) through α7-nAChR activation. Inhibition of α7-nAChR, either via receptor antagonists or siRNA-mediated knockdown, effectively suppressed NNK-induced cell migration, confirming that this effect is specifically mediated by α7-nAChR[84]. Moreover, both nicotine and NNK have been reported to activate nAChRs and β-adrenergic receptors via MAPK and COX-2/PGE2 signaling, leading to increased GC cell proliferation. These findings align with Wong et al’s study[85], which demonstrated that nicotine directly acts on β-adrenergic receptors, promoting the growth and angiogenesis of tumors within the gastrointestinal tract. Such evidence suggests a functional interplay between α7-nAChR and β-adrenergic receptors in nicotine-induced GC progression. Additionally, nicotine enhances angiogenesis, tumor invasion, and metastatic potential through α7-nAChR-mediated activation of the COX-2/EGF/VEGFR signaling axis[86,87]. Recent studies have revealed that nicotine upregulates IL-8 expression in AGS cells through ROS/NF-κB and ROS/MAPK (Erk1/2, p38)/AP-1 pathways, subsequently stimulating endothelial cell proliferation and tumor-associated angiogenesis[88]. Furthermore, α7-nAChR knockdown sensitized GC cells to taxanes, 5-FU, and ixabepilone, suggesting a role in drug resistance[89-91]. These findings provide critical insights into the potential utility of α7-nAChR expression as a predictive biomarker for chemotherapy efficacy in GC (Figure 2).

Figure 2 The interaction between gastric nerve system and gastric cancer. Neurotransmitters released from the fibers of the gastric nervous system modulate gastric cancer progression by engaging specific receptors that control proliferation, invasion, migration, angiogenesis, and immune responses. Tumor cell growth and motility are enhanced by norepinephrine/epinephrine through theβ2-AR pathway, which signals via PKA/STAT3. Acetylcholine, produced both by gastric carcinoma cells and enteric ganglia, triggers oncogenic Hippo and EGFR signaling in malignant cells via M3 receptor activation. Nicotine and structurally related compounds facilitate gastric tumor development through α5-nAChR-driven PI3K or ERK pathways, while also promoting angiogenesis and suppressing antitumor immune activity via α7-nAChR-mediated ROS/MAPK signaling. Furthermore, gastric ganglia release nerve growth factor (NGF) to support tumor expansion, whereas gastric cancer cells in turn secrete NGF to stimulate neurite extension, forming a self-perpetuating neuro-tumoral feedback circuit (by figdraw.com, Supplementary material). Ach: Acetylcholine; NGF: Nerve growth factor; NE: Norepinephrine; E: Epinephrine.

AMINO ACID NEUROTRANSMITTERS

Amino acid neurotransmitters, including GABA and glutamate, play dual roles in neural signaling and metabolic regulation[12]. Within normal gastric tissues, glutamate contributes to the modulation of gastric acid secretion and the preservation of mucosal integrity[92], while GABA exerts inhibitory effects that regulate smooth muscle contraction and facilitate mucosal repair[93]. Collectively, these neurotransmitters are essential for preserving gastric homeostasis. In the context of GC, their roles become more intricate and ambivalent[94]. GABA, through its receptors, has been implicated in suppressing the invasive potential of certain GC cells. Conversely, glutamate enhances tumor cell proliferation, migration, and metastasis by engaging glutamate receptors such as metabotropic glutamate receptors (mGluRs). Glycine receptor activation has been associated with increased chemosensitivity, whereas tryptophan metabolites—such as kynurenine—promote immune evasion by depleting tryptophan in the TME, thereby attenuating T-cell function[95]. Moreover, pharmacological interventions targeting glutamate metabolism, including mGluR inhibitors, have demonstrated promise in preclinical models as potential therapeutic strategies for restricting tumor progression[96].

GABA and GC

GABA is distributed throughout both the central and peripheral nervous systems[97,98]. Within the central nervous system, GABA primarily functions as an inhibitory neurotransmitter, modulating energy dynamics in GABAergic neurons[99]. In the peripheral nervous system, it is found in neurons of the enteric plexus, where it similarly serves as a neurotransmitter within the digestive tract[100]. GABA receptors are classified into two major categories: Ligand-gated ionotropic receptors, including GABA-A and GABA-C, and G-protein-coupled metabotropic GABA-B receptors. These receptors regulate the release of neurotransmitters such as ACh in the intestinal nervous system, thereby affecting gastrointestinal motility and gastric acid secretion[101]. Matuszek et al’s research[102] was the first to discover elevated levels of GABA expression in GC. The results showed that muscimol, a GABA-A receptor agonist, significantly reduced the incidence of chemically induced gastric tumors from 50% to 15%. Tumor-derived GABA has been implicated in the activation of β-catenin signaling, which contributes to tumor progression[103]. Research conducted by Maemura et al[104] demonstrated that GABA facilitated the proliferation of KATO III GC cells through autocrine and paracrine mechanisms via the GABA-A receptor, leading to the upregulation of MAP kinase and cyclin D1 expression. Recent research highlights the δ subunit of GABRD as a potential contributor to malignant phenotypes. GABRD mRNA is upregulated in tumor specimens, correlating with poor prognosis in preclinical analyses. Silencing GABRD or inhibiting its function in vitro reduced proliferation and invasion while promoting apoptosis[105]. Additionally, GABRD may influence the TME: 4-acetylaminobutyric acid activation of GABRD on CD8⁺ T cells inhibited AKT1 signaling, reducing T cell activation and infiltration. Blockade of this pathway in mouse models enhanced responses to immune checkpoint inhibition, suggesting a potential therapeutic avenue[103,106]. GABRD may also upregulate CCND1, further supporting proliferation and invasion in GC cells, though these findings remain largely preclinical[107]. Overall, GABA signaling appears to exert both pro- and anti-tumor effects depending on receptor subtype and cellular context. Clinical evidence remains scarce, and further translational studies are needed to clarify the relevance of these mechanisms in human GC.

Glutamate and GC

Glutamate serves as the primary excitatory neurotransmitter, with receptors categorized as mGluRs (mGlu1-mGlu8) and ionotropic glutamate receptors, including NMDA, AMPA, and kainate subtypes[108]. Beyond its role in excitotoxicity, functional Glu signaling has been implicated in tumorigenesis and cancer progression[109]. In GC, GRIK2, a member of the ionotropic Glu receptor family, has been associated with growth suppression and inhibition of tumor cell migration[110]. Conversely, the glutamate ionotropic receptor GRIN2D appears to facilitate tumor progression by promoting calcium influx into GC cells and activating the p38 MAPK signaling cascade[111]. mGluRs have not been extensively studied in GC, but their tumor-promoting roles in other malignancies suggest potential relevance as therapeutic targets[13]. Beyond receptor-mediated effects, amino acid metabolism also modulates the efficacy of chemotherapy in GC. Alterations in glutamine, serine, and glycine levels have been shown to induce ubiquitination-mediated degradation of KDM4A, a process that enhances the responsiveness of GC cells to chemotherapeutic agents[95]. Collectively, these results indicate that glutamate-associated signaling and metabolic pathways could modulate tumor behavior and responses to therapy, although the majority of supporting data remain preclinical. Such observations offer a foundation for exploring targeted interventions in GC in future clinical settings.

PEPTIDE NEUROTRANSMITTERS

Peptide neurotransmitters are bioactive molecules composed of amino acids linked by peptide bonds, broadly distributed in both the central and peripheral nervous systems. These molecules play crucial roles in neural communication and physiological regulation. Representative members of this group include gastrin, cholecystokinin (CCK), somatostatin (SST), substance P (SP), and NPY. By interacting with their respective receptors, these neurotransmitters modulate diverse biological processes such as pain transmission, emotional regulation, metabolism, and gastrointestinal motility and secretion[112]. In normal gastric physiology, gastrin and SST contribute to the regulation of gastric acid secretion, while SP facilitate gastrointestinal contraction, thereby accelerating gastric emptying[113-115]. Additionally, calcitonin gene-related peptide has been shown to promote vasodilation in gastric blood vessels and enhance mucus secretion, aiding in the repair of mucosal injury[116]. In the context of GC, peptide neurotransmitters exhibit distinct pathological roles. The peptidergic signaling system plays a fundamental role in cancer progression, influencing key processes such as cell proliferation, migration, and angiogenesis[117]. Overexpression of gastrin has been linked to the activation of the MAPK/PI3K pathway via its interaction with the CCK2 receptor, driving cell proliferation, invasion, and angiogenesis[118]. Moreover, SP has been implicated in enhancing the proliferative, adhesive, migratory, and invasive capacities of MKN45 GC cells in vitro[119]. NPY exerts its tumor-promoting effects through Y2 receptor activation, facilitating angiogenesis and establishing an immunosuppressive TME that promotes metastasis[120]. In contrast, SST and its analogs, such as octreotide, function as inhibitors of EGF/VEGF signaling, thereby suppressing tumor progression and inducing apoptotic pathways[121].

Gastrointestinal hormones and GC

Gastrin, predominantly secreted by G cells in the gastric antrum, regulates acid secretion. Chronic hypergastrinemia, as observed in H. pylori infection or autoimmune gastritis, has been linked to mucosal hyperplasia and neoplastic changes in preclinical studies[122]. Certain GC cells exhibit the capacity for autocrine gastrin secretion, which, upon interaction with CCK2 receptors, activates downstream signaling cascades, including the MEK and PI3K pathways. This activation promotes cyclin D1 expression, enhances proliferative activity, and suppresses apoptotic processes by upregulating anti-apoptotic proteins such as Bcl-2[123,124]. Furthermore, gastrin facilitates cancer cell invasion and migration through β-catenin and snail-mediated repression of E-cadherin expression[125]. Additionally, it induces VEGF secretion, fostering angiogenesis and sustaining metastatic progression[126]. However, findings by Zu et al[127] suggest that excessive gastrin levels may exert tumor-suppressive effects by activating the ERK-P65-miR-23a/27a/24 axis, introducing a nuanced perspective on its dual role in gastric malignancy.

CCK, a peptide hormone secreted by I cells of the small intestine, functions as both a gastrointestinal regulator and a neurotransmitter within the central and peripheral nervous systems. Its biological effects are mediated through two G protein-coupled receptors, CCK1R and CCK2R. Notably, CCK2R is frequently overexpressed in GC, making it a potential prognostic biomarker and therapeutic target[128]. CCK cooperates with gastrin to amplify oncogenic signaling through the MAPK and PI3K pathways, thereby accelerating tumor progression[123,124,129]. Research by Sun et al[130] demonstrated that co-administration of CCK2R inhibitors alongside COX-2 inhibitors significantly enhances apoptosis and suppresses GC cell proliferation.

SST, a neuropeptide synthesized by the hypothalamus, gastroenteropancreatic neuroendocrine cells, and peripheral nervous system, predominantly exists in two biologically active isoforms, SST-14 and SST-28. Its functions are mediated by binding to SST receptors (SSTR1-SSTR5)[131]. SST exerts strong antitumor properties in GC by inhibiting tumor development and progression[132]. The SST analog octreotide has been found to suppress GC cell proliferation and induce apoptosis through activation of SSTR3 in SSTR3-expressing gastric tumors[133]. Moreover, a study by Zhao et al[134] reported that SSTR1 expression is downregulated in GC, and its overexpression significantly impairs tumor cell proliferation, migration, and invasion. These findings suggest a promising avenue for the development of novel targeted therapies against GC.

SP and GC

SP, a key member of the tachykinin family, originates from the preprotachykinin A gene. Its biological effects are predominantly mediated through the NK1R, a GPCR[135]. Upon binding to NK1R, SP activates multiple tumor-promoting pathways, including PI3K, MAPK, and canonical Wnt signaling, contributing to cancer progression[136]. Early clinical studies led by Wilander et al[137] discovered SP immune reactivity in certain gastrointestinal malignancies. Tatsuta et al[138] demonstrated that prolonged SP administration in Wistar rats elevated both the incidence of MNNG-induced gastric tumors and the abnormal gastric mucosal marker index. These early observations underscore the necessity of elucidating the underlying mechanisms, with particular emphasis on the overexpression of NK1R in GC cells[119,135,139]. The presence of NK1R has been confirmed in human gastric carcinoma tissues as well as in the GC cell, where SP stimulation enhances proliferation, adhesion, migration, and invasion in vitro[119]. SP, a capsaicin-sensitive sensory neuropeptide, can induce acute inflammatory responses by increasing vasodilation and extravasation in the neuro-immune-metabolic axis, and SP enhances immunomodulation of mesenchymal stem cells through IL-2/IFN-g secretion in T cells[140,141]. Muñoz et al’s research[142] on nuclear expression patterns in GC cells revealed that SP exhibits higher nuclear localization in malignant cells compared to normal counterparts. Conversely, the NK1R antagonists L-732138 can effectively suppress gastrointestinal tumor cell proliferation and induce apoptosis in GC cells[143]. In addition, recent studies by Guo et al[144] demonstrated that exosomal miR-877-5p inhibits SP-driven GC cell proliferation, further supporting its potential as a therapeutic avenue. Although these data support a potential pro-tumor role for SP, direct evidence in human GC remains limited, and translational studies are needed to confirm clinical relevance.

NPY and GC

NPY, a crucial component of the pancreatic polypeptide family, serves as a neurotransmitter distributed throughout both the central and peripheral nervous systems[145]. This family also includes PP and PYY, with NPY exerting its biological effects primarily through interactions with five receptor subtypes, particularly Y1 and Y2 receptors. Recent research has implicated NPY in the pathogenesis and advancement of multiple malignancies, including brain tumors, breast carcinoma, cholangiocarcinoma, colorectal malignancies, esophageal cancer, and Ewing sarcoma[146-150]. However, the precise molecular mechanisms underlying NPY's role in GC remain largely unexplored. In early studies, Bilchik et al[151] conducted animal model studies on genetically predisposed gastric neuroendocrine tumors, demonstrating that the loss of gastric parietal cells could accelerate tumor development, the elevated serum and tumor tissue PYY concentrations were detected in these models. In contrast, a case report by Solt et al[152] documented increased PP levels in a GC patient. Furthermore, reduced plasma NPY levels in individuals with colorectal or GC were linked to both tumor burden and weight loss[149]. In the context of cancer prognosis, plasma Y1R levels have been proposed as potential biomarkers for metastasis and disease progression, as elevated Y1R expression correlates with lymphatic dissemination, advanced disease stage, perineural invasion, and diminished cancer-specific survival[15,153]. Extensive investigations suggest that antagonists targeting YR receptors not only inhibit cancer cell proliferation and tumor neovascularization—such as the Y2R antagonist BIIE0246, which reduces melanoma tumor mass, angiogenesis, and serum VEGF levels—but also induce direct tumor cell apoptosis[120,154]. Meanwhile, Y5R agonists promote VEGF release from breast cancer cells, fostering angiogenesis, further substantiating the tumor-suppressive potential of YR antagonism[147]. Clinical evidence remains scarce, although plasma Y1R levels have been proposed as potential biomarkers for disease progression and metastasis.

PURINE NEUROTRANSMITTERS

Purine neurotransmitters, typified by ADO and ATP, constitute a class of low-molecular-weight signaling molecules that exert regulatory effects by interacting with purinergic receptors, including the P1 and P2 receptor families. These neurotransmitters are extensively distributed across both central and peripheral nervous systems, where they participate in immune modulation, inflammatory cascades, and the remodeling of the TME. In recent years, their involvement in oncogenesis and cancer progression has garnered increasing scientific interest. Increasing evidence from preclinical studies indicates that purinergic signaling may participate in cancer-related processes, and dysregulation of these pathways has been reported in GC, suggesting potential therapeutic relevance[155].

ADO and GC

ADO, a purine-derived neurotransmitter and metabolic byproduct, modulates immune responses, tumor growth, and resistance to therapy through activation of purinergic receptors such as A2A and A2B within the TME. In recent years, its role in GC pathogenesis and potential therapeutic interventions has gained significant research interest. Preclinical data indicate that A2B receptor expression is elevated in GC tissues and may influence EMT markers, contributing to enhanced metastatic traits in cell line models[156]. A study by Liu et al[157] demonstrated that blocking the A2A receptor preserves the stem-like characteristics of GC cells by triggering the PI3K signaling cascade, thereby contributing to radiation resistance in MFC and MKN-45 cell lines. Investigations into ADO-mediated signaling and its implications for immunotherapy have intensified in recent years. ADO synthesis is primarily catalyzed by CD73, encoded by the NT5E gene, which converts AMP into ADO. Elevated CD73 expression in GC has been closely associated with poorer patient prognosis and reduced survival rates. By engaging A2A receptors on immune cells, including T lymphocytes and natural killer cells, ADO suppresses immune infiltration and function, fostering an immunosuppressive microenvironment that facilitates tumor immune evasion. Furthermore, ADO signaling enhances PD-L1 expression in malignant cells, thereby promoting resistance to immune checkpoint blockade therapies[14,158]. While these findings underscore a potential role of ADO in tumor immune evasion, clinical validation remains limited.

ADO triphosphate and GC

ADO triphosphate, a fundamental molecule in cellular energy metabolism, also functions as a critical neurotransmitter, exerting diverse effects on GC through its interaction with distinct purinergic receptors. Preclinical studies have shown that ATP facilitates the proliferation, migration, and invasion of GC cells by engaging the P2X7 receptor. Both ATP and its analog BzATP increase intracellular calcium levels, promote cytoskeletal reorganization, and enhance cell survival in vitro. Conversely, pharmacological blockade of P2X7R with antagonists such as A438079 or AZD9056 reduces these effects, suggesting potential therapeutic value in experimental models[159]. The involvement of ATP in the P2 purinergic signaling network within GC cells plays a crucial role in modulating tumor progression, particularly by fostering tumor cell proliferation and invasion[155]. Moreover, the ATP-P2X7R axis has been implicated in both oncogenesis and cancer-associated pain, underscoring its significance as a potential therapeutic target[160]. Beyond its direct effects, ATP has been found to act in synergy with NE to drive GC progression. This cooperative interaction enhances the invasive potential of GC cells by promoting EMT, further emphasizing the complexity of ATP-mediated oncogenic mechanisms[161] (Figure 3).

Figure 3 The interaction between serotonin, γ-aminobutyric acid, substance P, adenosine and gastric cancer. Neurotransmitters from the monoamine, amino acid, peptide, and purine classes—namely serotonin (5-HT), γ-aminobutyric acid (GABA), substance P (SP), and adenosine (ADO)—interact with overexpressed receptors on gastric carcinoma cells, leading to the activation of distinct intracellular signaling networks. In particular, 5-HT engages HTR2B to stimulate the PI3K pathway, which supports cellular survival and proliferation while suppressing ferroptosis and apoptosis; through HTR1D, it further drives proliferative activity. GABA primarily connects with MAPK signaling, thereby fostering tumor expansion and metabolic reprogramming. SP triggers immune mediators such as IL-2, amplifying inflammatory responses. ADO, acting via A2A/B-dependent PI3K signaling, promotes tumor development and upregulates PD-L1 expression, enabling immune escape. Collectively, these ligand-receptor interactions initiate pathway-specific cascades that converge on hallmark tumor phenotypes, including growth, migration, invasion, and immune modulation, highlighting their diverse contributions to gastric carcinoma progression (by figdraw.com, Supplementary material). 5-HT: Serotonin; GABA: Γ-aminobutyric acid; SP: Substance P; ADO: Adenosine; TME: Tumor microenvironment.

CONCLUSION

This study comprehensively reviews the regulatory roles of diverse neurotransmitters in GC initiation and progression, proposing an innovative therapeutic approach that targets specific receptor agonists or antagonists based on prior research findings. Monoaminergic neurotransmitters, such as NE and DA, have been shown to markedly drive the aggressive phenotypes of GC cells—including enhanced proliferation, migration, invasion, and neovascularization—primarily through activation of key signaling cascades like the β-adrenergic receptor pathway. It is worth noting that most neurotransmitters exhibit environment-dependent effects. For example, although DA typically suppresses GC via D2R, studies indicate that excessively high DA concentrations in vivo can also impair Teffs through D1R, leading to immunosuppression. This reflects the contradictory effects of neurotransmitters on GC under different conditions. Within the serotonergic system, HTR2B receptor engagement stimulates GC cell growth via downstream mediators such as the PI3K and MAPK pathways. Conversely, the roles of other 5-HT receptor subtypes remain poorly characterized and demand comprehensive evaluation in gastric malignancy. Despite increasing attention to the influence of the HPA axis in cancer biology, the precise contribution of this stress-responsive endocrine axis—particularly its key mediators such as E—within the gastric TME remains largely unexplored. In terms of cholinergic regulation, ACh facilitates oncogenic processes through both mAChR and nAChR receptors, yet the molecular interplay between these receptor classes within a single gastric tumor subtype has not been mechanistically dissected. GABAergic signaling is implicated in gastric tumorigenesis through the elevated expression of GABA-A and GABA-B receptors, which potentiate tumor progression via activation of mTOR signaling; however, head-to-head comparisons of antagonists targeting these receptors are still lacking. Although increased levels of SP and NPY have been detected in gastric carcinoma cells, detailed mechanistic understanding of their functional roles remains in its infancy. ADO receptor A2B is notably overexpressed in GC tissues, and ADO itself has been implicated in promoting resistance to immune checkpoint blockade. Moreover, ATP-mediated stimulation of P2X7 receptors drives tumor cell proliferation, motility, and invasiveness, yet differential and potentially synergistic effects of ATP in its capacity as an exogenous metabolite vs a neurotransmitter have yet to be delineated. The dynamic crosstalk between neural signaling molecules and the TME is emerging as a critical axis in GC research. Dissecting the complex regulatory networks governed by distinct neurotransmitter systems in gastric tumors will not only deepen our molecular understanding of gastric carcinogenesis, but also pave the way for novel biomarker discovery based on neurotransmitter-receptor expression profiles. Targeted therapeutic interventions utilizing receptor-specific agonists or antagonists may offer promising avenues for treatment. Furthermore, neurotransmitter-modulating strategies have the potential to synergize with immune checkpoint inhibitors to overcome therapeutic resistance. Unraveling the integrative signaling logic and inter-receptor communication among these neuromodulatory systems may guide the development of rational combinatorial regimens. Ultimately, precision-targeted modulation of neurotransmitter receptors could serve as a transformative approach in the personalized management of GC, offering new hope for improved survival outcomes.