Neurotransmitters in cancer: how receptor signaling and posttranslational modifications modulate tumor progression and offer new therapeutic targets.

Introduction

Neurotransmitters, which serve as essential signaling molecules that facilitate communication between neurons and effector cells, have garnered increasing attention because of their roles in tumorigenesis, tumor progression, and immune modulation. Based on their distinct chemical structures, neurotransmitters are primarily categorized into four groups [ 1 ]: (1) monoamines, including catecholamines (epinephrine (E), norepinephrine (NE), and dopamine (DA)), serotonin (5-hydroxytryptamine (5-HT), and histamine, among others; (2) cholinergic neurotransmitters, with acetylcholine (ACh) as the principal example; (3) amino acids, encompassing excitatory neurotransmitters such as glutamic acid and aspartic acid, as well as inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA), glycine, and taurine; and (4) peptides, which include substances such as substance P, vasopressin, and endogenous opioid peptides. Numerous studies have shown that neurotransmitters not only affect nervous system functions but also play a crucial role in modulating immune responses [ 2 ]. They play crucial roles in modulating the proliferation, migration, and invasion of tumor cells, as well as impacting the function of immune cells [ 3 ].

Neurotransmitters exert precise regulatory control over the function of target cells via two principal mechanisms: receptor-mediated signaling and posttranslational modifications (PTMs) of proteins [ 4 ]. Specifically, neurotransmitter membrane receptors, including G protein-coupled receptors (GPCRs) and ion channel-type receptors, initiate second messenger cascades, such as the cyclic AMP (cAMP) and IP3/Ca 2+ pathways, upon neurotransmitter binding. This process rapidly modulates ion channel opening, enzyme activity, and gene transcription. Furthermore, intracellular receptors directly facilitate the nuclear signal transduction of lipid-soluble neurotransmitters, such as steroid hormones, thereby influencing epigenetic modifications and long-term gene expression. Additionally, PTMs dynamically regulate the stability, localization, and interaction networks of target proteins through covalent modifications, such as monoaminylation (protein serotonylation and histone dopaminylation). The activation of classical 5-HT2A receptors triggers intracellular calcium (Ca 2+ ) release. This Ca 2+ flux serves as a critical cofactor that activates transglutaminase 2 (TGM2) [ 5 ]. Subsequently, this receptor-driven TGM2 activation catalyzes the covalent attachment of cytosolic serotonin to the glutamine residues (i.e., serotonylation) of specific target proteins, including small GTPases (e.g., Rab3a, Rab27a, Rab4, RhoA) and histone [ 6 – 8 ]. Through this cascade, neurotransmitters modulate tumor progression and immune cell functions via both intracellular signaling pathways and epigenetic reprogramming (Fig. 1 ).

For example, the recently discovered dopaminylation of histone H3 at glutamine 5 (H3Q5dop) is significantly enriched in colorectal and breast tumors [ 9 – 11 ]. Serotonylation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) increases glycolytic activity, thereby augmenting the antitumor function of CD8⁺ T cells. Neurotransmitter receptor signaling can activate key enzymes involved in PTMs, while PTMs facilitate the precise regulation and termination of signaling by modifying the receptors themselves or downstream signaling molecules. This multilayered regulatory network not only ensures the rapidity and specificity of neurotransmitter transmission but also provides a dynamic regulatory foundation for complex physiological processes, such as neuroimmune modulation.

In recent years, a growing body of research has investigated the potential application of specific neurotransmitters in tumor immunotherapy. Notably, serotonylation, as a form of PTMs, can enhance the glycolytic metabolism of CD8 + T cells, thereby increasing their efficacy in antitumor immune responses [ 12 ]. Additionally, GABA accumulates anomalously in various tumors, promoting tumor growth and facilitating immune evasion through multiple pathways [ 13 ]. These findings suggest that by modulating the synthesis, release, and signal transduction of certain neurotransmitters, novel and effective strategies for tumor immunotherapy may be developed. Moreover, the integration of neurotransmitter antagonists or inhibitors with immunotherapeutic approaches, such as immune checkpoint inhibitors [ 14 ], has been shown to increase patient survival rates to a certain degree [ 15 ]. The development of tumor vaccines [ 16 ] also represents a highly intriguing area of research. This article explores recent advancements in understanding the roles of key neurotransmitters in regulating tumor development and progression, with an emphasis on increasing the efficacy of tumor immunotherapy. The objective is to provide novel insights and methodologies for future immunotherapeutic strategies targeting tumors.

Neurotransmitters and their receptors: key modulators of intracellular signaling pathways and the immune microenvironment in cancer

Catecholamines serve as stress neurohormones to modulate tumor progression

Catecholamines, including E, NE, and DA, are derived from L-tyrosine and share a common chemical structure consisting of a benzene ring with two adjacent hydroxyl groups (-OH) and an amine group (-NH₂) side chain. Subsequently, L-DOPA is transformed into DA through the catalytic activity of aromatic L-amino acid decarboxylase (AAAD) [ 17 ]. Dopamine-β-hydroxylase (DBH) then converts DA into NE. This process is followed by the methylation of NE, a reaction catalyzed by phenylethanolamine-N-methyltransferase (PNMT), ultimately resulting in the formation of E. Tetrahydrobiopterin (BH4) is an essential cofactor throughout the catecholamine biosynthesis pathway (Fig. 2 a and b).

Previous studies have shown that long-term mental stress can activate the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system [ 18 ], increasing the levels of catecholamine neurotransmitters. Therefore, catecholamine neurotransmitters are also known as stress neurohormones. Elevated levels of catecholamine neurotransmitters accelerate the development of various cancers, including ovarian cancer, breast cancer, gastric cancer and colorectal cancer (CRC) [ 17 ].

Epinephrine and norepinephrine

E and NE are primarily secreted by the adrenal medulla and the sympathetic nervous system. Their effects are mediated by α- and β-adrenergic receptors, which belong to the family of 7-transmembrane G protein-coupled receptors [ 19 ]. Due to the extensive expression of adrenergic receptors in mammalian tissues, E and NE are involved in multiple mechanisms that facilitate tumor development. Specifically, N and NE regulate tumor progression not only by influencing cancer cell proliferation, survival, and migration but also by reshaping the immune environment through the activation of endothelial cells, immune cells, and fibroblasts [ 20 ].

Chronic stress has been shown to increase catecholamine production and activate β1/2-adrenergic receptors (β1/2-AR), thereby accelerating the progression of cancers [ 21 ], including CRC. The primary mechanism involves the activation of the β2-AR/PKA/CREB1 signaling pathway (Table 1 ), which exerts oncogenic effects on CRC cell lines such as HT-29, SW480, MC38, and CT26 through the phosphorylation of CREB1 [ 22 , 23 ]. In individuals with hepatocellular carcinoma (HCC), the β1-adrenergic receptor (β1-AR) increases the activation and effector functions of FOXP 3+ CXCR 3+ mucosal-associated invariant T (MAIT) cells via the ADRB1 signaling pathway [ 24 ](Table 1 ). Additionally, β2-adrenergic receptor (β2-AR) responds to isoproterenol (ISO) stimulation, which simultaneously activates Cdc42 and its downstream pathways, promoting the migration and invasion [ 25 ] of pancreatic ductal adenocarcinoma (PDAC) cells. Furthermore, β2-AR increases c-myc expression via PCBP2, thereby facilitating the growth of PDAC cells [ 26 ]. A study demonstrated that adrenergic neurogenic norepinephrine can alter endothelial cell metabolism, induce angiogenesis, and increase tumor growth in a mouse model of prostate cancer [ 27 ]. β2-AR modulates the frequency, survival, and functionality of myeloid-derived suppressor cells (MDSCs) and influences T-cell proliferation [ 28 ] by regulating the expression of immunosuppressive molecules. The activation of adrenergic receptors can result in increased expression of molecules such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), thereby promoting the growth and angiogenesis of gastric and ovarian cancers [ 29 , 30 ]. Catecholamines can activate the cAMP‒PKA signaling pathway via the β2-adrenergic receptor, resulting in the inhibition of glycolytic metabolism in CD8⁺ T cells and the suppression of the expression of effector molecules, such as interferon-gamma (IFN-γ) and granzyme B. Concurrently, this activation leads to the upregulation of programmed cell death protein 1 (PD-1) and TIM-3, thereby inducing terminal exhaustion in these cells [ 31 ]. Additionally, catecholamines contribute to the maintenance of myeloid-derived suppressor cell survival while simultaneously increasing the expression of PD-L1 and arginase 1. These processes collectively contribute to the establishment of an immunosuppressive microenvironment. Furthermore, our research revealed that noradrenaline (NE) signaling shares the GPCR–cAMP pathway with that of other monoamines, including DA and 5-HT. However, it also exhibits distinct dichotomies in receptor function. At the same synaptic location, NE is capable of exerting negative feedback to inhibit its own release via the presynaptic α2 receptor [ 32 ] while concurrently increasing the excitability of target neurons through the postsynaptic β receptor. This dual action results in a complex regulatory pattern characterized by “local inhibition and overall excitation”. Nevertheless, the complex molecular mechanisms involving NE and E in cancer remain to be fully elucidated.

Moreover, the modulation of the immune microenvironment through adrenergic receptor signaling can also elicit an antitumor effect. The activation of β2-AR induces the phenotypic transformation of TCR-γδ T cells through the NKG2D-dependent signaling pathway (Table 1 ), thereby enhancing multiple functional attributes of these lymphocytes, including their mobilization efficiency, ex vivo expansion capacity, and antitumor efficacy against human multiple myeloma [ 33 ]. Additionally, anti-CD40 agonistic antibodies (αCD40) stimulate dendritic cells (DCs), increasing their antigen-presenting capabilities and their ability to activate cytotoxic T cells. This process results in a counteractive effect on tumors with relatively low immunogenicity. In contrast, the activation of β2-AR modulates the CD40 signaling pathway in DCs by directly inhibiting the phosphorylation of IκBα and indirectly increasing the levels of phosphorylated cAMP response element-binding protein (pCREB) [ 34 ]. β-Adrenergic signaling is also involved in mediating inhibitory immune responses against tumors. The growth and size of tumors are affected by the increase in the number of antigen-specific CD8 + T cells and their effector phenotypes within the tumor microenvironment [ 50 , 51 ]. The attenuation of β2-adrenergic signal transduction is associated with an increased frequency of effector CD8 + T cells and an increased effector CD8 + T-cell to CD4 + regulatory T-cell ratio. Additionally, the population of CD8 + T cells expressing PD-1 within the B16 tumor microenvironment is reduced. The immunosuppressive mechanisms within the tumor microenvironment can limit the efficacy of anticancer vaccines. Therefore, studies have indicated that enhancing the priming of CD8 + T cells in tumor-draining lymph nodes and targeting β-adrenergic receptor signaling could improve the antitumor effects of anticancer vaccines [ 52 ].

Dopamine

In addition to modulating cardiovascular and renal functions as well as the secretion of various anterior pituitary hormones, the monoamine neurotransmitter DA is also associated with tumor progression. Dopamine receptors are categorized into two groups: D1-like receptors (D1 and D5) and D2-like receptors (D2, D3, and D4). These receptors play crucial roles in signal transduction processes in tumors, which involve GPCRs, downstream effector molecules, and metabolic enzymes. In contrast to E and NE, DA has distinct therapeutic potential because it inhibits angiogenesis, increases the efficacy of immunotherapy and potentiates immune function.

DA has been shown to restrict tumor growth by inhibiting angiogenesis within tumors [ 53 ]. In human gastric cancer tissues, low-dose DA treatment significantly delays tumor angiogenesis by inhibiting VEGFR-2 phosphorylation in tumor endothelial cells through the suppression of D2 receptor expression [ 54 ](Table 1 ). These findings suggest the potential application of DA as an antiangiogenic agent in the treatment of gastric cancer [ 36 ]. Furthermore, DA reduces the expression of ZO-1, Claudin-5, and CD31 in endothelial cells by inhibiting the Wnt/β-catenin signaling pathway via D1 receptor activity [ 55 ](Table 1 ). This inhibition disrupts junctional protein expression in cerebral microvascular endothelial cells, consequently compromising the integrity of the blood‒brain barrier (BBB) [ 35 ].

Dopamine receptors engage in a diverse array of signal transduction pathways by coupling with distinct G protein subtypes, such as Gαs/olf and Gαi/o, thereby inducing a wide range of physiological effects at the cellular level. The activation of D1 receptors enhances anti-inflammatory responses by increasing intracellular cAMP levels, which subsequently suppress the expression of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). This mechanism contributes to the reduction in tumor-associated inflammation in pancreatic and lung cancers [ 56 ]. Conversely, the activation of D2-like receptors inhibits the proliferation of breast cancer cells and promotes apoptosis by downregulating the activity of the PI3K/AKT/mTOR signaling pathway [ 57 ](Table 1 ) (Fig. 3 ). Moreover, the activation of D1–D2 receptor heterodimers initiates PLC-mediated hydrolysis of PIP2 through an interaction with Gq proteins. This process results in the production of diacylglycerol (DAG) and inositol trisphosphate (IP3), which function to activate protein kinase C (PKC) and facilitate the release of Ca 2+ from the endoplasmic reticulum, respectively. Simultaneously, these mechanisms interact with D1-regulated ion channels (K + /Na + /Ca 2+ ) to collectively contribute to cellular signal transduction processes. DA predominantly exerts its regulatory effects in a slow and diffusive manner through GPCRs, specifically the D1 type (D1 and D5) and D2 type (D2, D3, and D4) receptors, thereby modulating various brain functions, such as motivation, reward, and movement. A notable contradiction arises within the same brain region, such as the striatum, where the activation of D1 receptors via the direct pathway facilitates movement, whereas the activation of D2 receptors via the indirect pathway inhibits movement. These opposing functions coexist within the same microcircuit [ 58 ]. Furthermore, dopamine has dual roles in mental disorders: hyperactivity of dopaminergic function is linked to the positive symptoms of schizophrenia, whereas a deficiency of dopaminergic activity is associated with the motor symptoms of Parkinson’s disease [ 59 ]. This phenomenon of “the same neurotransmitter, opposite regulation” necessitates a nuanced understanding of receptor subtypes, projection pathways, and disease stages to elucidate the complex roles of dopamine in both physiological and pathological contexts. Although the precise mechanisms remain unclear, research has indicated that psychological stress may contribute to tumor progression, impair antitumor immune responses, and diminish the effectiveness of immunotherapy [ 60 ]. Chronic stress is posited to expedite the progression of glioblastoma (GBM) through the upregulation of DA and DRD2 levels [ 61 ]. This facilitative effect involves intricate signal transduction pathways, including the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), the inhibition of GSK3β, and the activation of β-catenin [ 62 , 63 ]. Src kinase is integral to various signaling pathways that regulate key cellular functions in ovarian cancer, contributing to cancer cell invasion and angiogenesis. By inhibiting the VEGF-induced activation of Src kinase, DA reduces vascular permeability mediated by VEGF [ 64 ]. DA and DRD2 agonists have long been utilized in the clinical management of Parkinson’s disease, hyperprolactinemia, and cardiovascular and renal disorders. These pharmacological agents may represent a novel approach to mitigate the impact of chronic stress on tumor growth [ 65 ]. However, their potential side effects, including nausea, hallucinations, and orthostatic hypotension, require careful monitoring.

Serotonin/5-hydroxytryptamine

Due to its initial discovery in serum, 5-HT is also known as serotonin. 5-HT is synthesized from the essential amino acid tryptophan. Initially, tryptophan is metabolized by the enzyme tryptophan hydroxylase (TPH) to yield the intermediate compound 5-hydroxytryptophan (5-HTP) [ 66 ]. Subsequently, 5-HTP undergoes decarboxylation by the enzyme AAAD, resulting in the formation of 5-HT (Fig. 2 c). The majority of serotonin, approximately 90%, is sequestered within the gastrointestinal tract, while the remainder is distributed throughout the central nervous system. Following synthesis, 5-HT translocates from the cytosol into intracellular vesicles via vesicular monoamine transporters (VMAT1 and VMAT2) [ 67 ]. Thereafter, the serotonin transporter (SERT) mediates the Na⁺-dependent reuptake of extracellular 5-HT to terminate its activity and recycle it back into the cell [ 68 ]. Serotonin receptors are categorized into seven distinct subfamilies, encompassing two primary subtypes: GPCRs and ligand-gated ion channel receptors. Notably, all serotonin receptors, with the exception of the 5-HT3 subtype, are GPCRs, which exert their physiological effects through the activation of secondary messenger pathways [ 69 ]. Recently, cytosolic serotonin-mediated protein serotonylation, which is catalyzed by transglutaminases (TGMs), has been shown to play a significant role in tumors and will be discussed in the next section.

The proliferation, metastasis, and drug resistance of cancer can be modulated by 5-HT through various receptors, which engage multiple signal transduction pathways [ 70 ] (Fig. 3 ). 5-HT facilitates the activation of autophagy and the STAT3 signaling pathway in tumor cells via 5-HT1A receptors, concurrently leading to the upregulation of programmed death-ligand 1 (PD-L1). In the periphery, 5-HT exerts an inhibitory effect on antitumor immune responses. Additionally, oxidative stress mediated by monoamine oxidase A (MAO-A) induces the polarization of tumor-associated macrophages toward the M2 phenotype [ 71 ]. HTR2B significantly promotes the growth of PDAC cells while inhibiting their apoptosis. This mechanism involves the synergistic actions of 5-HT and Fyn, facilitating the formation of the HTR2B–LYN–p85 complex, which subsequently activates the PI3K–AKT–mTOR pathway and the Warburg effect by upregulating MYC and HIF1A protein levels. The evidence indicates that HTR2B can regulate the PI3K/AKT/mTOR pathway, thereby increasing cellular survival in pancreatic and gastric cancers [ 39 , 40 ]. Furthermore, 5-HT participates in nonconventional signal transduction pathways. For example, the HTR1B/1D/1F receptors, which are prominently expressed in colorectal cancer stem cells (CSCs), interact with 5-HT to activate the Wnt/β-catenin signaling pathway. This activation occurs through the inhibition of β-catenin degradation, thereby promoting the self-renewal capabilities of colorectal CSCs and facilitating tumorigenesis [ 42 ]. Different subtypes of 5-HT receptors can elicit markedly divergent electrophysiological effects. For example, the 5-HT1A receptor, which is coupled to Gi/o proteins, inhibits adenylate cyclase activity and subsequently reduces neuronal excitability. In contrast, the 5-HT4 receptor, which is associated with GPCRs, increases cAMP production [ 72 ], thereby increasing neuronal excitability. Furthermore, the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) typically manifest after several weeks of treatment [ 73 ], indicating that their efficacy is not directly attributable to an immediate increase in 5-HT levels. Instead, their effects are achieved through the adaptive remodeling of downstream glutamatergic and GABAergic networks. This phenomenon underscores the temporal discrepancy inherent in the 5-HT system, wherein a pronounced disjunction exists between the immediate pharmacological effects and the delayed clinical outcomes. Additionally, 5-HT significantly increases the ability of tumor cells to evade ferroptosis. The underlying mechanism involves 5-HT acting as a potent antioxidant that neutralizes free radicals, thereby reducing ROS levels in cells and lipids. This reduction in ROS production subsequently decreases lipid peroxidation and mitigates ferroptosis [ 39 , 74 ].

Aberrant 5-HT metabolism has been implicated in accelerating tumor development, underscoring the importance of investigating the mechanisms underlying 5-HT metabolism as potential therapeutic targets in cancer treatment [ 75 ]. In studies focusing on CRC associated with colitis, 5-HT plays dual roles in disease initiation and progression. In the early stages, 5-HT impedes cancer initiation by modulating the transforming growth factor-beta (TGF-β) signaling pathway [ 76 ](Table 1 ). However, in later stages, it facilitates cancer progression through aberrant TGF-β signaling pathways, including the PI3K–AKT pathway and angiogenesis [ 41 ].

In addition to its previously discussed functions, 5-HT plays a crucial role in the tumor microenvironment. Modulating 5-HT levels, either by reducing its concentration or by inhibiting its release from platelets, can impede tumor progression, promote the infiltration of CD8 + T cells, and decrease PD-L1 expression.

Acetylcholine and nicotinic acetylcholine receptors

ACh functions as a neurotransmitter in the parasympathetic nervous system. It is synthesized from choline and acetyl coenzyme A as substrates, culminating in the formation of the final product through the catalytic action of choline acetyltransferase (also known as the choline acetylation enzyme, CAT) (Fig. 2 d). Its physiological role is modulated by nicotinic and muscarinic Ach receptors located in both the central and peripheral nervous systems. ACh is essential for neural signaling and plays a critical role in the regulation of the cardiovascular system, gastrointestinal tract, urinary tract, and cognitive processes.

Under conditions of chronic stress, the release of CXCL2 is increased, leading to the migration of neutrophils to the lungs. When subjected to stress, lung epithelial cells can secrete ACh. This mechanism substantially increases the formation of neutrophil extracellular traps (NETs), underscoring the pivotal role of epithelial cell-derived ACh induced by chronic stress in the remodeling of the premetastatic niche in breast cancer [ 77 ]. In the context of liver cancer development, Ach promotes the epithelial–mesenchymal transition and increases matrix metalloproteinase activity in HepG2 cells, thereby playing crucial roles in cell growth and migration. Solanine, a glycoalkaloid that is present in various plant species, acts as a competitive antagonist of nicotinic acetylcholine receptors (nAChRs). This compound inhibits tumor cell proliferation by disrupting neural signaling pathways and modulates microRNA-21 expression through nAChR-dependent mechanisms, thereby suppressing the growth of A549 lung carcinoma cells and reducing the progression of extrahepatic metastasis [ 43 , 44 ]. In the gastric mucosa, Dclk1 + endocrine cells and neurons are the primary producers of ACh, which regulates the gastric epithelial environment through ACh production. ACh can stimulate the expression of nerve growth factor (NGF), and excessive NGF expression further promotes the expansion of intestinal nerves and accelerates cancer development [ 78 ]. Tumorigenesis and epithelial cell proliferation can be inhibited by targeting Dclk1 + cells or the NGF/Trk signaling pathway (Table 1 ). This inhibitory effect is partially mediated by a mechanism involving the M3 muscarinic acetylcholine receptor. Regulating the ACh–NGF axis [ 46 ] is expected to impede the initiation and progression of gastric cancer. The expression of the muscarinic acetylcholine receptor subtype M4 (CHRM4) is inversely correlated with the suppression of AR signaling in prostate carcinoma [ 79 ]. Persistent inhibition of AR signaling may lead to the simultaneous downregulation of AR-responsive biomarkers and the upregulation of CHRM4 in prostate cancer cells via the CHRM4/AKT/MYCN signaling pathway (Table 1 ). These findings highlight a potential novel therapeutic target for the treatment of prostate cancer [ 47 ].

Experimental observations at the cellular level indicate that the α5 nicotinic acetylcholine receptor subunit (α5-nAChR) triggers STAT3 phosphorylation cascades in A549 and H1299 cells (Table 1 ). Subsequently, phosphorylated STAT3 interacts with the promoter region of CD47, increasing CD47 expression. These interconnected processes contribute to the accelerated progression of lung adenocarcinoma (LUAD) and the establishment of an immunosuppressive microenvironment [ 45 ]. In stage III and IV CRC, the expression levels of PD-L1, muscarinic acetylcholine receptor type 3 (M3R), and choline acetyltransferase (ChAT) are significantly increased. These alterations are strongly correlated with high-risk CRC and shorter survival of patients [ 79 ].

Within the tumor microenvironment, neurotransmitters collectively facilitate tumor immune evasion and resistance to immune checkpoint inhibitors by modulating immune checkpoint expression, inducing T-cell exhaustion, and promoting the immunosuppressive polarization of myeloid cells. For example, Ach activates the JAK2/STAT3 signaling pathway via the α7-nicotinic receptor, leading to the upregulation of PD-L1 expression in tumor cells and fostering the exhaustion phenotype of CD8 + T cells [ 80 ]. Additionally, GABA stabilizes PD-L1 protein levels in tumor cells through the GABAB receptor, inhibits the secretion of CCL4 and CCL5, and decreases the infiltration of CD8 + T cells. Concurrently, GABA derived from B cells induces the polarization of IL-10-producing macrophages, thereby enhancing myeloid cell-mediated immunosuppression.

γ-aminobutyric acid

The synthesis of GABA employs glutamate as the precursor substrate and is facilitated by the catalytic actions of glutamate decarboxylase (GAD) in conjunction with pyridoxal phosphate (Fig. 2 e). GABA serves as the principal inhibitory neurotransmitter within the central nervous system. During development, it acts as a trophic factor, regulating the proliferation, migration, differentiation, and apoptosis of neuronal cells. Three distinct classes of GABA receptors, designated A, B, and C, have been characterized based on their differential sensitivities to specific agonists and antagonists.

In various cancer cell types, GABA influences signal transduction and contributes to tumor progression [ 81 ]. GABA derived from B cells plays a pivotal role in modulating the immune system by promoting the differentiation of monocytes into macrophages with anti-inflammatory properties. These macrophages can secrete interleukin-10 (IL-10) and suppress the cytotoxic activity of CD8 + T cells [ 82 ]. In PDAC tissues, the expression of the gamma-aminobutyric acid type A receptor pi subunit (GABRP) is significantly increased and is strongly associated with tumor progression, metastasis, and poor clinical outcomes [ 83 ]. Through its interaction with KCNN4, GABRP induces an influx of Ca 2+ , which subsequently activates the NF-κB signaling pathway (Table 1 ), leading to increased expression of CXCL5 and CCL20 and promoting macrophage infiltration. These findings suggest that targeting GABRP or KCNN4 may represent a promising therapeutic strategy for PDAC [ 48 ]. Additionally, in primary gastric cancer tissues [ 84 ], the GABRD mRNA is highly expressed, indicating that the δ subunit of the γ-aminobutyric acid A-type receptor may serve as a potential therapeutic target [ 85 ]. GABA is recognized as the principal inhibitory neurotransmitter within the central nervous system. However, its effects are not without notable contradictions. GABA facilitates rapid inhibition via GABAA receptors, which are ionotropic chloride channels, and mediates slow presynaptic inhibition through GABAB receptors, which are metabotropic and coupled to Gi/o proteins. Nonetheless, in immature neurons or under certain pathological conditions, such as hypoxia or epilepsy, elevated intracellular chloride concentrations [ 86 ] can result in the activation of GABAA receptors, leading to depolarization or even excitatory responses [ 87 ]. Furthermore, in certain neural circuits, particularly during developmental phases or specific behavioral states, GABA and glutamate demonstrate synergistic rather than antagonistic interactions, collaboratively modulating network oscillations [ 88 ]. This paradox, in which an “inhibitory neurotransmitter becomes excitatory,” highlights that the function of GABA is contingent upon intracellular and extracellular ion gradients and the developmental stage, thereby challenging the simplistic characterization of the function of GABA as merely inhibitory.

The emergence of drug-resistant tumors poses a significant challenge in cancer therapy, and altering the cellular metabolism of these tumor cells represents a promising strategy to mitigate this issue. Recent studies utilizing [ 89 ] high-throughput metabolomics have shown that MnO₂ nanoparticles can modulate GABA metabolism in cancer cells, thereby reconstructing the immune tumor microenvironment (iTME). This technology holds substantial potential for preventing the recurrence and metastasis of renal cell carcinoma.

Glutamate decarboxylase 67 (GAD67), a pivotal enzyme involved in the biosynthesis of GABA, is integral to both tumor progression and the immune system’s antitumor response. Research has indicated that the deletion of the GAD67 gene significantly impedes tumor growth and can increase the efficacy of immune checkpoint blockade (ICB) therapy, thereby overcoming resistance to immunotherapy. The subsequent interaction between GABAA and GABAB receptors results in the inhibition of GSK-3β kinase activity, which in turn enhances β-catenin signal transduction [ 90 ]. This molecular sequence culminates in β-catenin-driven immune evasion through the exclusion of DCs and T cells, thereby promoting malignant proliferation within the tumor microenvironment [ 49 ]. Furthermore, benzodiazepines have been shown to increase GABAA receptor-mediated anion transport in melanoma cells, resulting in cellular depolarization and reduced cell viability. The combined application of benzodiazepines, radiotherapy, and anti-programmed death-ligand 1 (α-PD-L1) therapy nearly completely eradicates tumors. Additionally, this therapeutic combination exerts significant systemic therapeutic effects by promoting the infiltration of multifunctional CD8 + T cells [ 91 ].

Substance P

Substance P is widely distributed across the mammalian central nervous system, peripheral nervous system, and nonneuronal tissues, where it is involved in a range of physiological and pathological processes. As a neurotransmitter, this undecapeptide plays a crucial regulatory role in nociceptive transmission, emotional homeostasis, and neural–immune interactions, thereby performing diverse biological activities across multiple systems.

Substance P plays critical roles in tumor angiogenesis and proliferation through its interaction with the neurokinin 1 receptor (NK-1R), which is highly important in the pathology of vascular abnormalities [ 37 ]. Specifically, substance P facilitates tumor cell proliferation, migration (including invasion and metastasis), and antiapoptotic processes and increases the efficiency of glycolysis, thereby promoting tumor growth and metabolic activity. Conversely, antagonists of NK-1R have been shown to induce apoptosis in tumor cells and inhibit both tumor growth and metastasis. Consequently, the substance P/NK-1R axis represents a promising therapeutic target for cancer treatment [ 38 ].

Substance P has promising therapeutic potential in the context of cancer immunotherapy because of its immunomodulatory properties. Experimental evidence indicates that this neuropeptide significantly enhances the phagocytic function of macrophages, a crucial factor in strengthening antitumor immune responses. Both in vitro and in vivo models have shown that the SP-mediated increase in the phagocytic capacity facilitates the effective clearance of malignant cells, thereby leading to the measurable suppression of tumor growth [ 92 ]. However, it also underscores the necessity for comprehensive translational research to refine its therapeutic window and optimize delivery methods in oncological applications.

The involvement of substance P in tumor immunotherapy is potentially linked to its effect on the modulation of immune checkpoint expression. Immune checkpoints represent a series of inhibitory pathways that are integral to the immune system and play crucial roles in preserving self-tolerance and modulating the duration and intensity of physiological immune responses [ 93 ]. Researchers are investigating approaches to bolster the antitumor immune response and increase the effectiveness of immunotherapy by modulating immune checkpoint expression. Intrinsic immune checkpoint molecules within tumor cells, such as TIGIT, can facilitate tumor progression by suppressing the functions of NK cells and CD8 + T cells [ 94 ]. Consequently, substance P may influence the effectiveness of tumor immunotherapy through its regulation of immune checkpoint expression. A more comprehensive understanding of the regulatory mechanisms governing immune checkpoints, as well as the influence of the tumor microenvironment on immunotherapy, will be instrumental in advancing the development of more efficacious immunotherapeutic strategies.

Neuropeptide Y

Neuropeptide Y (NPY) is a 36-amino-acid polypeptide that is extensively distributed throughout the central and peripheral nervous systems in mammals, making it one of the most prevalent neuropeptides. As a member of the pancreatic polypeptide family, NPY plays crucial roles in numerous physiological functions, including the maintenance of homeostasis, mood regulation, inhibition of reproductive processes, and modulation of muscle excitation [ 95 ]. The physiological and pathological effects of NPY are mediated primarily through its interactions with specific receptors, such as the Y1, Y2, and Y5 receptors.

NPY plays multifaceted roles in tumorigenesis and tumor progression. On the one hand, NPY overexpression can inhibit tumor progression in certain contexts [ 96 ]. For example, research has indicated that ETV5 enhances the neuronal differentiation [ 97 ] of neuroblastoma by downregulating neurogenin 2 expression. Conversely, NPY contributes to tumor growth and progression. In HCC, ETV5 contributes to tumor progression and metastasis by increasing the recruitment and activation of polymorphonuclear MDSCs [ 98 ]. Similarly, in esophageal squamous cell carcinoma, ETV5 increases tumor metastasis by upregulating the expression of SKA1 and TRPV2 [ 99 ].

NPY may modulate the efficacy of immunotherapy against tumors by influencing the effectiveness of tumor vaccines [ 100 ]. First, research has indicated that the induction of immunogenic cell death (ICD) in tumor cells can markedly increase the efficacy of tumor vaccines [ 101 ]. Second, NPY may increase the effectiveness of tumor vaccines through synergistic interactions with other immunotherapeutic strategies. For instance, the evidence suggests that the combination of immune checkpoint inhibitors with tumor vaccines can substantially amplify antitumor immune responses [ 102 , 103 ]. Consequently, NPY may potentiate the efficacy of tumor vaccines by synergizing with immune checkpoint inhibitors.

Neurotransmitters mediate posttranslational modifications: emerging modulators of the tumor and immune microenvironments

In addition to classic receptor-mediated tumor development, emerging evidence has revealed that intercellular neurotransmitters can modulate signaling pathways and immune responses through PTMs. In particular, TGM2-mediated monoaminylation of histones and nonhistone proteins, such as dopaminylation and serotonylation, significantly affects tumor progression.

Dopaminylation

TGM2 catalyzes PTMs of proteins, including monoaminylation, via the transamidation of various glutamine-containing protein substrates. It mediates the formation of histone dopaminylation (H3Q5dop), which regulates gene expression and plays a critical role in the dysregulation associated with psychiatric disorders and substance addiction. Furthermore, protein dopaminylation acts as a regulatory mechanism that counteracts ferroptosis, suggesting that the TGM2–TPI1 axis is a novel therapeutic target for lung injury and fibrotic diseases [ 104 ]. Well-designed chemical probes have been utilized to enrich for dopaminylated proteins in colorectal cancer cells through biorthogonal chemistry, followed by a comprehensive chemical proteomic analysis. These findings reveal a significant link between protein dopaminylation and cancer development, indicating that inhibiting this modification may represent a promising anticancer strategy. While numerous studies have focused on the role of dopaminylation in neuroplasticity, its functions in tumor progression and the immune microenvironment remain underexplored.

Serotonylation

In addition to the receptor-dependent mechanism, 5-HT can facilitate signal transmission independently of receptors through a process known as serotonylation [ 70 ]. Protein serotonylation is a posttranslational modification characterized by the covalent attachment of 5-HT to the glutamine residues of target proteins, and is facilitated by the catalytic activity of TGMs, such as TGM2. This modification plays important roles in various pathophysiological processes by modifying a range of proteins, including small GTPases (e.g., Rab4 and RhoA), histone H3, and cytoskeletal proteins such as α-actin and β-actin [ 105 ](Fig. 3 ). Research has demonstrated [ 106 ] that PDAC patients exhibit increased levels of histone serotonylation, particularly H3K4me3Q5ser, along with its catalytic enzyme, TGM2 [ 107 ]. The inhibition of this process has been shown to suppress tumor progression. Another study revealed that suppressing histone serotonylation not only impedes EPN tumorigenesis but also modulates the expression of a key group of developmental transcription factors. These findings provide insights into the intricate interplay among neuronal signaling, neuroepigenomics, and developmental processes in driving brain cancer malignanc [ 108 ]. Our research group has identified a serotonylation mechanism involving GAPDH, which enhances glycolytic metabolism and the antitumor immune function of CD8 + T cells via the hydroxypropionylation reaction mediated by TGM2 within tissues. Consequently, this mechanism amplifies the antitumor efficacy of CD8 + T cells.

The importance of histone serotonylation in tumor progression is evident. The conversion of cancer-associated fibroblasts (CAFs) into the inflammatory-like CAF (iCAF) subtype is initiated by histone H3Q5ser, which subsequently increases proliferation, invasion, and macrophage polarization in CRC cells [ 76 ].

Emerging strategies in cancer therapy that target neurotransmitters

Drug repositioning

Neurotransmitter receptor inhibitors represent promising therapeutic candidates

Since N and NE facilitate cancer progression via adrenergic receptor signaling, antagonists of E and NE receptors are currently being evaluated as innovative therapeutic strategies for the prevention of cancer development [ 109 , 110 ]. Propranolol, a nonselective β1 and β2 adrenergic receptor antagonist that is commonly used to treat cardiovascular diseases, has shown significant efficacy in impeding the progression of subcutaneous CT26 CRC and AOM/DSS-induced CRC in animal models. In addition, propranolol inhibits tumor growth and increases chemotherapy sensitivity in breast, ovarian, and pancreatic cancer [ 111 , 112 ]. Mechanistically, β2-adrenergic antagonists can inhibit the cAMP/PKA and Ras-regulated MAPK pathways (Table 1 ), subsequently affecting the expression of transcription factors such as NF-κB, AP-1, and CREB, along with their associated genes. These changes substantially reduce cell invasion and proliferation and are essential for G1/S phase arrest and apoptosis in cancer cells [ 113 , 114 ]. Numerous clinical trials are currently investigating the use of propranolol in the treatment of various tumors, such as NCT05679193 for prostate cancer and NCT03245554 for gastric cancer. These findings underscore the importance of β-adrenergic receptor inhibitors in cancer therapy. Elevated DRD2 levels in patients with severe depression may correlate with a poor prognosis for patients with GBM. The combination of primaperone, a DRD2-specific inhibitor, with temozolomide represents a novel therapeutic strategy for GB [ 115 ]. Furthermore, the interaction between DRD2 and the von Hippel–Lindau (VHL) protein within the nuclei of tumor cells may activate a hypoxia-inducible factor 1-alpha (HIF1α) signaling pathway that is independent of hypoxic conditions (Table 1 ). This pathway is critical for tumor progression induced by psychological stress [ 116 ]. Trifluoperazine (TFP), a DRD2 antagonist, effectively inhibits melanoma tumor growth in stressed murine models by disrupting the interaction between DRD2 and VHL, thereby preventing the degradation of HIF1α [ 117 ].

In vitro studies have demonstrated that 5-HT can increase PD-L1 expression in both murine and human cancer cells by promoting glutamine acetylation, in which glutamine residues and 5-HT form a direct covalent bond, thereby activating small G proteins. In wild-type mice, a reduction in peripheral 5-HT levels has been shown to inhibit the growth of isogenic pancreatic and colorectal tumors and decrease PD-L1 expression. These findings suggest the potential clinical application [ 118 ] of drugs targeting 5-HT and PD-L1 inhibitors in managing tumor growth. In China, the primary strategy for preventing and treating nausea and vomiting involves the use of 5-HT3 receptor antagonists, such as remifentanil and granisetron, in combination with dexamethasone. By selectively inhibiting 5-HT3 receptors [ 119 ], these drugs mitigate chemotherapy-induced gastrointestinal side effects and effectively alleviate nausea and vomiting.

Acetylcholine receptor inhibitors, including both atropine and 4-DAMP, exert substantial inhibitory effects on colorectal cancer cells. Through the inhibition of the phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), these agents significantly impede the proliferative and migratory capacities of human-derived colorectal cancer cells and promote apoptotic processes [ 120 ].

Three-Mercaptopropionic acid (3-MPA), a specific inhibitor of glutamate decarboxylase 1 (GAD1), has shown substantial potential in treating cancer. This compound can impede the migration and invasion of oral cancer cells. When combined with ICB therapy, it increases antitumor efficacy [ 121 ]. It functions as an immunomodulator by exerting immunosuppressive effects on tumors, including inhibiting T-cell recruitment via DCs and directly suppressing T-cell activation, thereby influencing the malignant phenotype of the tumor [ 122 ]. The dysregulated overexpression of GAD1 within particular cancer cell populations redirects glutamine metabolic pathways toward the biosynthesis of GABA.

Targeting neurotransmitter levels

Existing studies [ 123 ] indicate that selective serotonin reuptake inhibitors (SSRIs) not only are effective at treating tumor-associated depression but also hold potential as first-line antitumor agents alone or in combination with conventional therapies for standard tumor treatment. In the context of pancreatic ductal carcinoma, SSRIs such as fluoxetine independently inhibit the activation of small GTPases and Rac1, thereby impeding disease progression. Further research is warranted to elucidate the role of 5-HT signaling in tumorigenesis and antitumor responses, which is vital for improving the prognosis of patients with cancer. Pharmacological interventions, such as the oral administration of fluoxetine or injections of telotristat, which inhibit tryptophan hydroxylase 1 (TPH1) and deplete serotonin, have the potential to increase the effectiveness of PD-1 checkpoint blockade. Consequently, the integration of serotonin-targeting agents with PD-1 inhibitors may represent novel avenues for cancer treatment.

Treatments targeting posttranslational modifications in tumors

A study revealed that TRIM28 can facilitate the recruitment of TGM2 to MYC, increasing the level of the H3Q3ser modification of genes targeted by MYC and promoting HCC progression. The progression of HCC can be significantly suppressed by targeting the transglutaminase activity of TGM2, which exerts a synergistic effect when it is combined with sorafenib. These findings provide a theoretical foundation for exploring new therapeutic strategies for liver cancer [ 124 , 125 ].

Progress in targeting neurotransmitters in tumor immunotherapy

Investigating the roles of neurotransmitters in tumor immunotherapy represents a prominent and well-regarded area of research. Increasing evidence indicates that neurotransmitters significantly influence tumor development, tumor progression, and immune evasion.

DA is being increasingly recognized for its emerging roles in tumors and the tumor microenvironment, particularly within the immune system. Its potential applications in tumor immunotherapy warrant further investigation [ 126 ]. Current research suggests that when used in conjunction with other immunotherapeutic strategies, DA may exert a more pronounced effect, indicating that the DA pathway could serve as a promising target for cancer treatment. Although DA does not directly interact with immune checkpoints, its influence on the immune system provides novel insights into the combined use of immune checkpoint inhibitors. Within the reactive oxygen species (ROS)-responsive nanocomplex, DA plays a crucial role in the response to ROS [ 127 ]. By cleaving the thioether bond, it facilitates the targeted and timely release of protein cargoes such as αPD-L1 and glucose oxidase (GOx). These proteins increase the efficacy of immunotherapy [ 128 ] based on ICB in the tumor, leading to a significant reduction in primary tumor growth and metastasis rates. Additionally, the use of antidepressants in conjunction with immune checkpoint inhibitors may further enhance the body’s antitumor immune response. In clinical practice, fluoxetine and monoamine oxidase inhibitors (MAOIs) are commonly employed as antidepressant medications. DA plays a pivotal role in immunoregulatory processes that facilitate the differentiation of CD8 + T cells into CD103 + tissue-resident memory T cells (TRMs) [ 129 ]. Moreover, this mechanism influences the antitumor immune response mediated by TRM cells against CRC, thereby underscoring the immunostimulatory function of DA signaling [ 130 ].

The expression of adrenergic receptor β1, a novel immune checkpoint [ 131 ], is upregulated on exhausted T cells. Research [ 63 ] has indicated that the ablation of β1-adrenergic signaling can inhibit the progression of T cells to an exhausted state during chronic infections. Furthermore, when combined with ICB in melanoma [ 132 ], this ablation significantly enhances the effector function of T cells. A notable correlation has been observed between the use of selective β1 receptor blockers in conjunction with pembrolizumab and prolonged recurrence-free survival of melanoma patients. In pancreatic cancer models, the combination of β-blockers and ICB exerts a synergistic effect on the treatment of PDAC. The results of the aforementioned studies suggest that the integration of β-receptor blockers with ICB may increase the antitumor efficacy of these agents in more immunogenic tumors [ 132 ]. Current research [ 133 ] highlights the immunosuppressive role of β2-AR on T cells, identifying it as a potential checkpoint target in chimeric antigen receptor T (CAR-T) cell therapy. When RNA interference was used to downregulate β2-AR expression in CAR-T cells, increased cytotoxic effects on prostate cancer cells were observed in vitro. Furthermore, the absence of β2-AR is associated with increased CAR-T-cell proliferation, an increased CD8 + /CD4 + T cell ratio [ 134 ], reduced apoptosis, and an increased proportion of T central memory cells. These findings provide a foundation for future investigations in clinical and translational CAR-T-cell research [ 132 ].

A research team has shown that neurotransmitters and neuropeptides, such as DA, glutamate, GnRH-II, NPY, and CGRP, either individually or in combination [ 135 ], can effectively decrease the proportion of PD-1 + T cells and the expression level of PD-1 in T cells from both healthy individuals and patients with HCC. Concurrently, these agents increase the proliferative capacity and cytotoxic efficacy of T cells against HCC cells. Future large-scale clinical trials involving cancer patients must be conducted to validate these observations and ensure the safety of these drugs. Sven Saussez et al. [ 136 ]. suggested that glutamate, DA, and GnRH-II may be utilized in a novel adoptive T-cell immunotherapy, which they termed “neuroimmunotherapy”. This approach is particularly relevant for certain patients with head and neck cancer (HNC) [ 135 ]. The methodology involves ex vivo activation of the patient’s T cells using glutamate salts, DA, or GnRH-II for a duration of 30 min, followed by the readministration of the activated T cells to the patient via intravenous or intratumoral routes. The clinical outcomes of patients are influenced by the type of disease, specific treatment regimen, and differences among individual patients.

Furthermore, MAO-A suppresses the immune function of antitumor T cells by regulating autocrine serotonin signaling in tumor cells. This study identifies MAO-A as a novel immune checkpoint and provides compelling evidence for the potential repurposing of MAOI antidepressants in cancer immunotherapy [ 137 ].

The efficacy of immunotherapy can be increased by integrating neurotransmitter inhibitors or antagonists with immunotherapeutic agents, such as immune checkpoint inhibitors [ 138 ]. This combined therapeutic approach has the potential to concurrently target multiple functions of tumor cells, thereby improving patients’ survival outcomes. In recent studies, innovative strategies have been developed to increase the delivery and effectiveness of cancer vaccines. For instance, a novel peptide-based tumor nanovaccine has been designed to increase antigen presentation and elicit effective antitumor immunity. Researchers have engineered nanoparticles capable of inducing dendritic cell activation and eliciting a robust CD8 + T cell response in vivo [ 139 ]. These nanoparticles, termed 8FNs, have demonstrated substantial therapeutic and preventive efficacy against tumor proliferation and metastasis. Furthermore, when combined with anti-programmed cell death PD-1 therapy, they exert a synergistic effect [ 140 ]. While therapeutic strategies that integrate immune checkpoint inhibitors with neurotransmitter antagonists are relatively novel, their clinical application faces several significant challenges [ 141 ]. Initially, the empirical foundation for these strategies was predominantly derived from preclinical models and lacks validation in comprehensive clinical trials [ 142 ]. Consequently, conclusions regarding their efficacy and safety must be interpreted with caution. Furthermore, this combined treatment may disrupt the balance of the “neuro–immune–tumor” tripartite interaction network [ 143 ], potentially resulting in unintended “nontargeted effects”. The “nontargeted effect” presents a dual challenge. The unexpected modulation of neurotransmitter receptors on immune cells can potentially increase antitumor efficacy [ 144 ]. Numerous approved neuropharmaceuticals, including SSRIs, antihypertensive agents, and antiepileptic drugs, represent promising options for repurposing existing medications [ 145 ]. However, during the initial stages of combined application, increased risks of neurotoxicity, autoimmune side effects [ 146 ], and systemic toxicity exist [ 147 ]. Furthermore, tumor heterogeneity and its reliance on the microenvironment contribute to the variability in the responses among different tumor types and even among distinct lesions within the same tumor to this combined therapeutic approach. Consequently, a singular strategy is unlikely to achieve broad applicability. Therefore, future research should focus on assessing the therapeutic window of combination therapies, developing patient stratification strategies based on biomarkers, and facilitating the rational transition of these therapies into clinical practice. Nonetheless, despite advancements in vaccine development, numerous challenges persist. For instance, the heterogeneity of tumor cells complicates the identification of a universal vaccine target. Immunosuppressive agents present within the tumor microenvironment may attenuate the immune response to vaccines and other therapeutic interventions, posing significant challenges that require resolution. Furthermore, investigations of neurotransmitter interactions with radiotherapy and chemotherapy constitute a complex and demanding field of study. Current research indicates that the use of specific neurotransmitter inhibitors can increase the efficacy of both radiotherapy and chemotherapy.

Although ICB therapy holds considerable potential for tumor treatment, its efficacy in glioma is constrained by the BBB. Nanoparticles targeting PD-L1 and engineered with nAChR and a choline transporter (ChT) expressed on the surface of the BBB can increase BBB penetration through receptor-mediated transport, suggesting a novel strategy for glioma immunotherapy [ 148 ].

Discussion

Emerging interdisciplinary approaches are at the forefront of neurotransmitter research, consistently improving our understanding of their roles in both physiological and pathological contexts.

Previous studies have demonstrated that individuals who engage in regular meditation practices exhibit elevated levels of GABA, a neurotransmitter that attenuates neural activity, thereby contributing to reduced anxiety and an improved mood. Furthermore, mindfulness meditation has been linked to increased 5-HT levels [ 149 ] and may modulate the function of the serotonin system by altering the DNA methylation status of the serotonin transporter gene Slc6a4 . This modulation could represent one of the potential molecular mechanisms by which mindfulness mitigates stress and improves mood. These neurobiological alterations can be assessed using functional magnetic resonance imaging (fMRI), magnetic resonance imaging (MRI), electroencephalography (EEG), and biomarkers such as neurotransmitter levels and cortical thickness. For cancer patients, mindfulness meditation serves as a nonpharmacological intervention that can alleviate treatment-related side effects and long-term effects [ 150 ]. Research has indicated that mindfulness-based interventions exert beneficial effects on depression, anxiety, and quality of life among patients with breast cancer [ 151 ], ovarian cancer [ 152 ], and metastatic non-small cell lung cancer [ 152 ], as well as their caregivers. While mindfulness meditation is purported to moderately influence the immune function of cancer patients by mitigating inflammation, increasing the count and activity of immune cells [ 153 ], and potentially increasing telomere length and activity, its biological effects remain incompletely understood, with variability observed across different biomarkers [ 154 ]. Consequently, more rigorously designed studies, standardized biomarker reporting, and investigations involving more diverse populations are needed to further elucidate the potential mechanisms and clinical applicability of mindfulness meditation in cancer treatment.

Recent research has revealed that neurotransmitters play dual roles in facilitating synaptic transmission and directly influencing epigenetic reprogramming. In the context of neuroendocrine prostate cancer (NEPC) [ 155 ], the neurotransmitter 5-HT accumulates intracellularly via synthesis mediated by DDC and reuptake dependent on SLC6A4. Subsequently, 5-HT is catalyzed by TGM2, leading to the serotonination of the Q5 residue on histone H3K4me3 (H3Q5ser). This posttranslational modification impedes the removal of H3K4me3 by the KDM5 family of demethylases through steric hindrance, thereby altering the genomic distribution of H3K4me3 and modulating the expression of genes associated with the epithelial–mesenchymal transition (EMT) and NEPC lineage maintenance, including Ezh2 , Sox9 , and Ascl1 . This mechanism highlights the role of serotonin as an epigenetic regulatory molecule that directly links neurotransmitter metabolism with tumor lineage plasticity. Targeting this pathway, for instance, through the use of the DDC inhibitor carbidopa, has been shown to effectively suppress NEPC growth, underscoring its potential for clinical intervention. Recent research has [ 156 ] demonstrated that cocaine can induce the reversible reprogramming of histone modifications in male germ cells through the activation of the dopamine D1 receptor (DRD1), thereby influencing the transcriptional regulation of genes and chromatin compaction. These studies have also highlighted the role of the dopamine system as a critical neurotransmitter signaling pathway in the epigenetic regulation of germ cells. Furthermore, the extracellular matrix (ECM) has been shown to modulate the therapeutic response of NEPC [ 157 ] to dopamine receptor D2 (DRD2) inhibitors by influencing the activity of the epigenetic factor Ezh2 . The specific type of ECM plays a pivotal role in determining sensitivity to DRD2 inhibitors, while Ezh2 inhibitors can counteract ECM-induced drug resistance through epigenetic reprogramming. These findings underscore the complex interplay among the ECM, epigenetics, and neurotransmitter signaling.

Moreover, the advent of single-cell and spatial transcriptomic techniques has significantly improved our understanding of neural–immune interactions. In an investigation into the mechanisms underlying chronic active multiple sclerosis (MS) [ 158 ], researchers discovered that IFN-γ produced by CD8 + T cells can suppress the expression of the cholesterol transporters ABCA1 and G1 in microglia. This suppression leads to cholesterol accumulation within cells, resulting in the production of “foam-like” microglia that perpetuate neuroinflammation. Through a spatial gradient analysis and prediction of cellular interactions, the researchers further identified the differential distribution of various glial cell types, such as MIMS, AIMS, STROLS, and DAOLs, within the core, margin, and surrounding white matter of the lesion. This analysis revealed the propagation pathways of inflammatory signals within the tissue space. In related research on Alzheimer’s disease (AD) [ 159 ], spatial transcriptomics has shown that disease-associated microglia and astrocytes exhibit nonrandom distributions in specific regions, including the corpus callosum, hippocampus, and deep cortex. These findings underscore the high regional specificity of neural–immune interactions. In a study of the human microglial cell atlas (HuMicA) [ 160 ], researchers integrated 19 single-cell and single-nucleus transcriptomic datasets and revealed that disease-associated macrophages (DIMs) and edge-related macrophages (MACs) are differentially distributed under varying pathological conditions. These findings suggest that the neural–immune response is characterized by both disease specificity and cell type specificity. The advancement of single-cell and spatial transcriptomic techniques, such as snRNA-seq, scRNA-seq, and MERFISH, has encouraged researchers to concurrently determine the cellular identity, transcriptional state, and precise spatial localization at single-cell resolution. This information provides unprecedented technical support for elucidating the dynamics and regional specificity of neural–immune interactions.

The interaction between metabolism and neural signaling has recently emerged as a prominent area of research. Empirical studies [ 161 ] have demonstrated that metabolites, including lactic acid, β-hydroxybutyric acid, and ATP/adenosine, can signal through targets such as GPCRs, thereby regulating neural network activity. Dysregulation of the lactate signaling pathway [ 161 ] is intricately linked to the pathological processes of various neurodegenerative diseases, including AD, ischemic brain injury, and frontotemporal dementia. Specifically, lactate can activate its receptor, hydroxycarboxylic acid receptor 1 (HCAR1), which activates the intracellular cAMP signaling pathway, consequently influencing synaptic plasticity, angiogenesis, and neuroinflammatory responses. Furthermore, intestinal metabolites [ 162 ], including short-chain fatty acids, bile acids, and tryptophan, function as signaling molecules that activate specific receptors and channels, such as GPR41/43 receptors, 5-HT3 receptors, and Trpa1 channels. The activation of these proteins subsequently stimulates the vagus nerve, leading to alterations in the morphology, activity, and release of inflammatory factors by microglia and thereby influencing the immune status of the central nervous system [ 163 ]. Consequently, targeting these intestinal metabolites and their associated neural signaling pathways holds promise as a novel strategy for intervening in neuroinflammation and related disorders.

This emerging paradigm substantially advances the systematic understanding of the multidimensional signaling roles of neurotransmitters. Furthermore, it facilitates the integration and evolution of theoretical frameworks at the intersection of mental health, oncology, and immunology. This paradigm offers a robust theoretical foundation and identifies potential targets with promising clinical translation prospects, thereby aiding the development of novel intervention strategies for a cross-diagnostic system.

Conclusions

Psychological stress and emotional factors significantly contribute to tumor progression and chemotherapy resistance through intricate neurotransmitter pathways. Empirical studies have demonstrated that chronic psychological stress can activate the HPA axis and the sympathetic nervous system [ 18 ], resulting in elevated levels of catecholamines, including adrenaline, noradrenaline, and DA. By binding to their specific receptors, these neurotransmitters not only directly promote tumor cell proliferation, migration, and invasion but also indirectly facilitate tumor progression by modulating the function of immune cells within the tumor microenvironment [ 164 ]. For example, the activation of adrenergic receptors can increase the survival of tumor cells and suppress antitumor immune responses, thereby contributing to chemotherapy resistance [ 165 ]. Furthermore, neurotransmitters such as DA can similarly influence tumor progression through analogous mechanisms. These findings underscore the pivotal roles of psychological stress and emotional factors in tumor development and provide a scientific foundation for the development of therapeutic strategies targeting neurotransmitter pathways in cancer.

These findings indicate that neuroreceptor inhibitors exhibit significant potential in cancer therapy [ 166 ]. Notably, SSRIs, such as fluoxetine, influence the equilibrium between tumor cell proliferation and apoptosis by modulating 5-HT levels in the tumor microenvironment [ 167 ]. This modulation increases the efficacy of immune checkpoint inhibitors. SSRIs function by blocking the reuptake of 5-HT, thereby increasing its concentration in the synaptic cleft, which in turn regulates the activity of tumor-associated immune cells, inhibits tumor growth, and increases chemotherapy sensitivity [ 168 ]. Furthermore, inhibitors targeting DA and acetylcholine receptors are being investigated. These inhibitors impede tumor cell proliferation, migration, and invasion through distinct molecular mechanisms, indicating a wide range of potential applications. The development and utilization of these neuroreceptor inhibitors provide novel strategies and approaches for cancer treatment and are anticipated to become integral components of comprehensive cancer therapy in the future.

Neurotransmitters play dual roles in the regulation of tumor cell biology: they not only directly affect but also significantly contribute to the intricate processes of protein PTMs. These modifications precisely regulate both histones and nonhistone proteins, thereby influencing tumorigenesis and tumor progression. Research has demonstrated that PTMs, such as the dopaminylation and serotonylation of histones, can alter chromatin structure and modulate the transcriptional activity of genes associated with tumors, consequently affecting tumor cell proliferation, migration, and apoptosis. For example, H3Q5dop is notably enriched in colorectal and breast tumors and is closely associated with tumor progression [ 169 ]. Consequently, therapeutic strategies targeting these P™ processes, such as the development of specific inhibitors to block the activity of key enzymes, represent novel approaches to impede tumor progression and enhance antitumor immune responses.

Drawing on the aforementioned information, these key findings introduce a novel perspective in the field of tumor treatment and indicate the intricate and pivotal roles of the neurotransmitter system in various processes, including tumor initiation, progression, metastasis, and prognosis. Concurrently, they underscore the substantial potential of the neurotransmitter system as a target for therapeutic intervention in tumor treatment, offering the promise of new breakthroughs and renewed hope in addressing tumor-related challenges.

Acknowledgements

Not applicable.

Abbreviations

Epinephrine

Norepinephrine

Dopamine

Serotonin /5-hydroxytryptamine

Acetylcholine

Gamma-aminobutyric Acid

Posttranslational Modifications

Glyceraldehyde-3-phosphate Dehydrogenase

Aromatic L-amino Acid Decarboxylase

Dopamine-β-hydroxylase

Phenylethanolamine-N-methyltransferase

Hepatocellular Carcinoma

Colorectal Cancer

Pancreatic Ductal Adenocarcinoma

Myeloid-derived Suppressor Cells

Glutamate Decarboxylase 1

Dendritic Cells

Colorectal Cancer Stem Cells

G protein-coupled Receptors

Programmed Death-ligand 1

Monoamine Oxidase A

Cyclic AMP

Tryptophan Hydroxylase

Nerve Growth Factor

Immune Tumor Microenvironment

Glutamate Decarboxylase

Gamma-aminobutyric Acid Type A Receptor Pi Subunit

Muscarinic Acetylcholine Receptor Subtype M4

Neuropeptide Y

Transglutaminase 2

Von Hippel-Lindau

Hypoxia-Inducible Factor 1-alpha

Vascular Endothelial Growth Factor

Selective Serotonin Reuptake Inhibitors

Immune Checkpoint Blockade

Blood-brain Barrier

Neuroendocrine Prostate Cancer

Alzheimer’s Disease

Authors' contributions

X.-Y. Ding was responsible for writing the main manuscript text.;H.-L. Liu, W.-R. Zhang and Y.-T. Zhang prepared Figure 1 ; D.-N. Zhao, M.-J. Guo and X. Yuan prepared Figure 2 . X. Wang and D. Feng designed the review. All authors reviewed the manuscript. Therefore, the authorship order reflects their chronological involvement in the project.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 32170910 and 82503232), Natural Science Foundation of Jiangsu Province (BK20250130 and BK20250560), and Jinshan Talents of High-level Talents Project in Medical Field (full-time doctor) [Grant No. JSYC2024-002 to D. Feng].

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xuanyin Ding and Hele Liu contributed equally to this work.

Contributor Information

Xu Wang, Email: jsdxwx@126.com.

Dan Feng, Email: dandanfung@163.com.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.