Neural regulation in lung cancer: from mechanisms to new therapeutic perspectives

Abstract

Lung cancer remains a leading cause of cancer-related deaths worldwide. Despite advances in targeted therapy and immunotherapy, treatment outcomes are often constrained by tumor heterogeneity and the complex tumor microenvironment. Recent studies highlight the critical role of the nervous system in lung cancer pathogenesis through bidirectional interactions between the central/peripheral nervous system and cancer cells. This review systematically explores how psychological stress, sleep disorders, and smoking influence the initiation and progression of lung cancer via neuroendocrine-immune networks. We further detail the dual roles of key neurotransmitters—including catecholamines, GABA, serotonin, dopamine, glutamate, histamine, and acetylcholine—in regulating tumor proliferation, epithelial-mesenchymal transition, angiogenesis, and immune evasion, with an emphasis on their context-dependent and receptor subtype-specific effects. Emerging evidence indicates that neurotransmitters remodel the tumor microenvironment by modulating immune cell function and receptor-mediated signaling pathways. We also discuss the therapeutic potential of neuromodulatory agents, particularly β-blockers and neurotransmitter receptor-targeted drugs, and their possible synergistic effects with conventional therapies, while critically distinguishing between strategies supported by clinical evidence and those remaining at the preclinical stage. Challenges persist, including neurotransmitter concentration gradients, receptor subtype specificity, and limitations of preclinical models. The convergence of neuroscience and oncology offers promising avenues for innovative lung cancer therapies, underscoring the necessity for interdisciplinary collaboration to translate these discoveries into clinical practice.

Graphical abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s10238-026-02278-1.

Introduction

Lung cancer ranks among the most common malignant tumors worldwide, characterized by high incidence, high mortality, and poor prognosis. Epidemiological data indicate that approximately 2 million new cases of lung cancer are diagnosed annually, resulting in 1.76 million deaths, making it the leading cause of cancer-related mortality globally [1–3]. In recent years, significant advances have been made in lung cancer treatment. However, surgery, chemotherapy, and radiotherapy remain the primary approaches. Due to the high metastatic potential of tumors, drug resistance (such as chemotherapy resistance and radiation resistance), and side effects, the five-year survival rate for patients remains only 10%–20% [4–6]. Targeted therapies based on advances in molecular biology, such as those targeting specific mutations in NSCLC, have significantly improved outcomes for some patients. However, issues of drug resistance and recurrence persist [7]. Immunotherapy has emerged as a research hotspot in recent years, enhancing antitumor immune responses through mechanisms like immune checkpoint inhibitors. Nevertheless, its clinical application continues to face challenges due to significant interindividual variability and limited efficacy [7–10].

Despite significant advances in targeted and immunotherapy in recent years, the heterogeneity of the tumor microenvironment (TME) remains a key factor contributing to treatment resistance and recurrence/metastasis [11]. Research indicates that the nervous system not only participates in the initiation of lung cancer but also engages in complex interactions with cancer cells through neurons, neurotransmitters, and various neuroactive molecules during tumor proliferation, invasion, and metastasis [12]. This neuro-tumor interaction has become a research hotspot in the field of cancer neuroscience [13]. In the lung cancer microenvironment, not only nerve fibers secrete neurotransmitters, but cancer cells and immune cells can also actively produce neurotransmitters. Through autocrine/paracrine actions, these neurotransmitters influence neurons and other cells. Furthermore, immune cells extensively express neurotransmitter receptors (such as dopamine receptors) on their surfaces, forming a tripartite interaction network among neurons, immune cells, and tumors [12, 14].

Neurotransmitters exhibit a pronounced double-edged sword effect in lung cancer: different neurotransmitters play distinct roles in tumor initiation and progression, and even within the same neurotransmitter system, the impact on tumors can vary dramatically under various conditions. This dual regulatory mechanism offers a unique perspective for developing novel anti-cancer strategies. Neurotransmitter receptors (NRs) are widely expressed in lung cancer cells, promoting tumor progression by regulating pathways such as the cell cycle, epithelial-mesenchymal transition (EMT), and angiogenesis [12]. They also remodel the tumor immune microenvironment, indirectly supporting tumor advancement by activating immune cells or endothelial cells to promote inflammatory responses [15, 16]. Conversely, certain non-neurotransmitter signaling molecules that participate in neuro-immune crosstalk—such as the cytokine/alarmin IL-33—have been shown to suppress the malignant progression of lung cancer by modulating immune responses and interfering with the tumor microenvironment [17]. In recent years, significant advances have been made in the field of tumor neuromodulation. The elucidation of multiple molecular mechanisms underlying neuro-tumor interactions has played a crucial role in developing novel therapeutic approaches by targeting key molecules.

In this review, we aimed to systematically explore how the nervous system contributes to the initiation and progression of lung cancer. While recent reviews, have elegantly summarized neuro-tumor interactions through the lens of cancer hallmarks, our work distinguishes itself through a distinct conceptual framework and focus. First, we structure our analysis around the dual origins of neural influence, examining the contributions of both the central nervous system (via psychological stress, sleep, and circadian disruption) and the peripheral nervous system (via autonomic innervation and neurotransmitter signaling). Second, we place a strong emphasis on the paradoxical, dual roles of specific neurotransmitters (e.g., serotonin, dopamine, and glutamate), detailing how they can exert both pro- and anti-tumorigenic effects depending on receptor subtypes, concentration gradients, and the local tumor microenvironment. Third, we provide a comprehensive, clinically-oriented overview of the translational landscape, critically assessing the therapeutic potential and current clinical evidence for a range of neuromodulatory agents, including not only β-blockers but also antidepressants, antipsychotics, and other receptor-targeting drugs. Finally, we explicitly address key bottlenecks and future challenges—such as neurotransmitter concentration gradients, receptor subtype specificity, and the limitations of preclinical models—that are pivotal for guiding future research and clinical translation. Through this integrative and multi-layered perspective, our review aims to provide a unique and actionable synthesis that complements and extends the existing literature, fostering a deeper understanding of the neurobiological underpinnings of lung cancer and accelerating the development of novel therapeutic strategies. Detailed information regarding the literature search strategy, databases, keywords, and inclusion criteria is provided in Supplementary Material 1.

Interactions between the central nervous system and lung cancer

Increasing research indicates a bidirectional interaction between the brain and tumors. The brain influences tumor cell biology through complex neural networks involving the peripheral, endocrine, and immune systems, while tumors can establish locally autonomous and sensory neural networks that transmit signals to the central nervous system, thereby affecting brain activity. In the development and progression of lung cancer, the central nervous system primarily exerts regulatory effects through neural-endocrine-immune networks [18]. Clinical and experimental studies indicate that psychological stress, depression, anxiety, circadian rhythm disruption, and smoking all promote the development of lung cancer (Fig. 1). These effects are primarily mediated through activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), leading to increased secretion of glucocorticoids and catecholamines, thereby impairing immune surveillance and promoting tumor growth [19, 20]. A deeper understanding of these mechanisms suggests that neuro-modulation therapies [21] could complement conventional treatments like surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, while simultaneously advancing interdisciplinary fields such as psychoneuroimmunology and neuro-oncology.

Fig. 1.

The role of different life-styles and health in the interaction between the Nervous System and lung cancer. (A) Exercise: Exercise regulates immunity, suppresses tumors, and improves lung health through multiple pathways. It promotes IL-33 release, enhancing inflammation control and immune surveillance. By activating AMPK and inhibiting the NLRP3 pathway, exercise directly suppresses cancer cell growth; simultaneously, it activates the HPA axis to further inhibit tumors. It restores miR-101 expression, participating in gene regulation to maintain pulmonary homeostasis. (B) Smoking: Smoking is a core risk factor for lung cancer, with its harm extending across molecular, cellular, and tissue levels. Nicotine in tobacco binds to nicotinic acetylcholine receptors, initiating downstream carcinogenic signaling. It induces the production of N2-type neutrophils, releasing miR-4466; simultaneously, it promotes brain metastasis through the SKI/SOX2/CPT1A pathway. (C) Sleep: Sleep quality significantly impacts pulmonary immunity and tumorigenesis. Adequate sleep maintains immune cell function and suppresses immunosuppression, neuroendocrine abnormalities, and chronic inflammation. Sleep disruption activates the sympathetic nervous system and HPA axis, releasing reactive oxygen species that cause DNA damage. It also promotes the release of stress hormones and catecholamines, which exacerbate inflammation and suppress immune surveillance via β-adrenergic receptors, ultimately promoting cancer cell proliferation. (D) Psychological Factors: Psychological states such as anxiety and depression influence lung cancer development through the neuro-immuno-endocrine axis. Anxiety and depression induce IL-33 release, which promotes cancer stemness and metastatic potential via abnormal neural circuits and neuroendocrine dysregulation. Concurrently, psychological issues exacerbate smoking behavior and neuroendocrine abnormalities, creating a vicious “psychological-behavioral-physiological” carcinogenic cycle. All figures were created using Adobe Illustrator (version 27.0, Adobe Inc., San Jose, CA, USA)

Exercise

In preclinical and translational studies, exercise has been shown to modulate the autonomic nervous system by activating the vagus nerve pathway, thereby suppressing pro-inflammatory immune responses while enhancing anti-tumor immunity (Fig. 1A). For example, exercise may exert dual regulatory effects (both suppressing inflammation and enhancing immune surveillance) in lung cancer by inhibiting the abnormal expression of IL-33 [17]—a cytokine/alarmin that functions as a molecular bridge in neuro-immune crosstalk, rather than a classical neurotransmitter. Additionally, in vitro experiments have demonstrated that exercise-conditioned serum can suppress lung cancer cell growth through the AMPK-dependent NLRP3 inflammasome regulatory pathway [22]. Exercise-induced hormonal changes (such as epinephrine and cortisol) can indirectly influence lung cancer progression by activating the hypothalamic-pituitary-adrenal axis. Animal studies indicate that catecholamines released after exercise activate the β-adrenergic receptor signaling pathway, thereby enhancing the tumor-killing capacity of natural killer (NK) cells [23, 24]. Clinical studies indicate that exercise interventions such as preoperative respiratory training can significantly reduce the incidence of postoperative pneumonia in lung cancer patients by improving vagus nerve-mediated pulmonary defense reflexes [25]. Personalized exercise programs can also improve postoperative fatigue and physical function by regulating autonomic nervous system balance. Research data show that the exercise group demonstrated increased distance in the 6-minute walk test at 2 months postoperatively compared to baseline (baseline: 467.9 m → postoperative: 482.2 m), while the standard care group showed a decrease (baseline: 481.4 m → postoperative: 471.5 m). The difference between the two groups was 22.7 m (P = 0.08), indicating no statistically significant difference was observed between the two groups at the conventional α = 0.05 level [26]. Preclinical evidence further suggests that exercise may influence lung cancer-related gene expression through neuroactivity-dependent epigenetic modifications, such as the regulation of microRNAs like miR-101 [27]. Clinical observations have indicated that approximately 29% of lung cancer patients exhibit miR-101 expression loss, raising the hypothesis that exercise might suppress tumor progression by restoring the function of such tumor-suppressing miRNAs, although this mechanism awaits direct clinical validation [27].

However, most current mechanism studies remain confined to animal models or in vitro experiments. The specific molecular targets of exercise-induced neuromodulation in lung cancer (such as the PAK3-Smad4 signaling axis [28] and the SH2B3-TGFβ1 pathway [29]) require further clinical validation [30, 31]. Furthermore, the specific effects of different exercise types (aerobic/resistance/flexibility training) on the nervous system require further differentiation [32].

Smoking

Nicotine, the primary addictive component in tobacco, affects the central nervous system by activating neuronal nicotinic acetylcholine receptors (nAChRs) (Fig. 1B). These receptors are ligand-gated ion channels composed of five transmembrane subunits and are widely distributed throughout the brain and peripheral nervous system [33]. Epigenetic alterations associated with smoking, such as DNA methylation, have been demonstrated to correlate with lung cancer development. These changes may influence neurodevelopment-related gene expression through neuro-tumor crosstalk [34, 35]. For instance, differential methylation patterns at specific CpG sites may explain why only some smokers ultimately develop lung cancer [36].

Preclinical investigations have suggested that therapeutic strategies targeting neuro-tumor interactions, such as nAChRs or the YAP regulatory pathway, may represent a novel direction for identifying gene therapy targets in smoking-related NSCLC [37], although these approaches remain at an experimental stage. Artificial intelligence (AI) also demonstrates significant potential in lung cancer prevention through smoking cessation support technologies. By monitoring smoking behavior via wearable device signals and assessing puffing characteristics during smoking, AI provides technical support for quitting [38].

It is important to emphasize that although smoking is the primary risk factor for lung cancer (accounting for approximately 90% of lung cancer deaths worldwide [33]), individual genetic differences and environmental factors contribute to variable susceptibility, with the lifetime risk of lung cancer among smokers estimated to range from approximately 10% to 20% across different studies and populations [36, 39, 40]. This disparity may partly stem from genetic polymorphisms in neuromodulatory pathways [40]. Multiple studies have also demonstrated that smokers exhibit superior responses to immune checkpoint inhibitors (ICIs) compared to non-smokers [41, 42]. This correlates with higher programmed death-ligand 1 (PD-L1) expression in the tumor microenvironment of smokers, while the CHRNA5 gene encoding the α5-nicotinic acetylcholine receptor (α5-nAChR) has also been implicated in lung cancer immunotherapy response [41, 42]. Meta-analyses indicate that for smokers, ICIs demonstrate significant superiority over chemotherapy regardless of monotherapy or combination therapy. Among never-smokers, both ICI monotherapy and dual-immunotherapy combinations show limited efficacy; however, ICI combination with chemotherapy still yields significant survival benefits and may represent a superior option [43]. Smoking status (current or former smoking) is a potential predictor of ICIs’ efficacy in patients with metastatic NSCLC [43]. Lung cancer tissues from smokers exhibit enrichment of tertiary lymphoid structures, which may promote antitumor immune responses [44]. Single-cell analysis also reveals that smoking status significantly influences TME heterogeneity, thereby modulating immunotherapy response [45]. Although some studies have not identified statistically significant differences in objective response rates (ORR) between smoking status groups, former smokers still exhibit a trend toward better immunotherapy response compared to current smokers and non-smokers [46]. Furthermore, the survival benefit among smokers is more pronounced in advanced lung cancer [47]. However, the mechanisms underlying smoking’s impact on immunotherapy remain incompletely understood. Beyond PD-L1 expression and tumor mutational burden (TMB), carcinogens in tobacco may influence immune responses through epigenetic modifications or metabolic reprogramming [48, 49].

Sleep

A prospective cohort study utilizing the UK Biobank dataset revealed a U-shaped association between sleep duration and lung cancer risk. Insufficient sleep (< 7 h) was associated with an 18% significantly elevated risk (HR = 1.18, 95% CI: 1.07–1.30; p = 9.35 × 10⁻⁴), while excessive sleep duration also demonstrated a statistically significant 17% risk increase (HR = 1.17, 95% CI: 1.02–1.34; p = 0.03) [50]. The mechanism involves neuroendocrine dysregulation, such as HPA axis disruption and hormonal imbalance, as well as reduced numbers and activity of immune cells like T cells and NK cells, leading to immunosuppressive effects (Fig. 1C). Excessive sleep may be associated with chronic inflammation or underlying diseases [51]. Night-type sleep patterns (sleeping late and waking late) carry a higher risk of lung cancer (HR = 1.25) compared to morning-type sleepers, potentially linked to disrupted melatonin secretion rhythms and impaired antioxidant effects [50]. Additionally, common sleep disorders such as insomnia and sleep apnea can increase sympathetic nervous system excitability and activate the HPA axis, leading to the release of stress hormones (e.g., cortisol) and catecholamines. These neurotransmitters can promote inflammatory responses in the tumor microenvironment through pathways like β-adrenergic receptors and suppress immune surveillance functions (e.g., by reducing natural killer cell activity), thereby accelerating the proliferation and metastasis of lung cancer cells [52]. Intermittent hypoxia caused by sleep apnea further exacerbates sympathetic nervous system excitation, leading to oxidative stress and DNA damage, with sex hormones playing a significant role in this process [52, 53].

Sleep disruption induces lung cancer through mechanisms that compromise immune homeostasis. Such disturbances suppress the secretion of antitumor cytokines including interferon-gamma (IFN-γ), while concurrently promoting the release of pro-inflammatory factors such as IL-6 and TNF-α. Additionally, they impair CD8 + T cell and dendritic cell functions, thereby weakening tumor antigen recognition [51]. Intermittent hypoxia caused by sleep apnea can upregulate HIF-1α, promoting tumor angiogenesis and EMT [52, 54, 55].

Sleep influences lung cancer progression through multi-level regulation of the neuroendocrine-immune network, involving mechanisms such as sympathetic overactivation, abnormal neurotransmitter signaling, impaired immune surveillance, and gender-specific inflammatory responses [53–55]. Interventions targeting sleep disorders—such as improving sleep apnea and regulating circadian rhythms—may represent potential strategies for lung cancer prevention and adjunctive therapy.

Psychological factors

Psychological factors, particularly anxiety and depression, often persist among lung cancer patients and are associated with poorer prognosis and increased mortality rates [56]. Large-scale prospective studies indicate that depressive and anxiety symptoms are significantly associated with the incidence of lung cancer and smoking-related cancers [57, 58]. In the minimally adjusted model, results showed that each one-standard deviation (SD) increase in depressive symptoms was associated with a significantly elevated risk of lung cancer incidence, with a HR of 1.15 (95% CI [1.08, 1.23]) and an I² heterogeneity index of 47% (95% CI [3%, 71%]). In the maximally adjusted model, after controlling for health-related covariates, the association between depressive symptoms and lung cancer incidence weakened, with the HR decreasing to 1.07 (95% CI [1.00, 1.15]) and the heterogeneity index I² at 36% (95% CI [0%, 66%]). Data on the association between anxiety symptoms and lung cancer incidence are as follows: In the minimal adjustment model, each 1 SD increase in anxiety symptoms was associated with a significant increase in lung cancer incidence risk, with an HR of 1.12 (95% CI [1.04, 1.21]) and an I² heterogeneity index of 19% (95% CI [0%, 62%]). In the maximally adjusted model, after controlling for health-related covariates, the association between anxiety symptoms and lung cancer incidence weakened, with HR decreasing to 1.07 (95% CI [1.00, 1.15]) and I² for heterogeneity at 0% (95% CI [0%, 71%]) [58]. Long-term depressive symptoms may increase lung cancer risk through direct (e.g., neuroendocrine pathways) or indirect (e.g., promoting smoking behavior) mechanisms, with smoking habits explaining approximately one-third of the association strength [58, 59] (Fig. 1D).

Tumor burden as a chronic stressor can induce anxiety. Animal models demonstrate that tumor-associated anxiety promotes tumor progression through neuro-tumor interactions (such as septal nucleus-mediated neural circuits) [60, 61]. Psychological stress may also influence the stemness and metastatic potential of lung cancer cells by releasing neurotrophic factors (such as IL-33) [17, 62]. In neuro-tumor interactions, neurons and glial cells directly or indirectly regulate tumor progression through synapses, neurotransmitters, and other mechanisms. As one of the molecules involved in immune-neural cross-regulation, IL-33 may serve as a bridge in this process [63, 64]. Therefore, the psycho-neuro-immune axis holds considerable therapeutic potential [65–69]. Preliminary studies suggest psychological factors (e.g., depression) may influence ICIs efficacy by modulating immune function, though specific mechanisms require further validation [65]. Mindfulness-based psychological interventions have been shown to alleviate anxiety, depression, and fatigue in lung cancer patients [66], while targeting neuromodulatory pathways (e.g., bidirectional immune regulation of IL-33) may guide novel combination therapies [17, 67]. A clinical study demonstrated that nurse-led psychological interventions have also been shown to significantly alleviate patients’ depression, anxiety, and fatigue, while greatly enhancing their quality of life [68]. Beyond these factors, the patient’s own risk perception and behavioral changes also play a significant role. Screening adherence among high-risk individuals for lung cancer is strongly associated with psychological factors such as risk perception and smoking cessation motivation, suggesting that psychological interventions can enhance early screening rates [70, 71]. Advances in neuroscience have identified novel targets for lung cancer treatment. It is recommended to establish interdisciplinary collaboration integrating psychology, neuroscience, and oncology to optimize therapeutic strategies.

Influence of the autonomic nervous system on lung cancer

Sympathetic nervous system

Previous studies have demonstrated that the sympathetic nervous system significantly influences the initiation, progression, and metastasis of lung cancer through multidimensional interactions within the neuro-immune-tumor microenvironment [12]. In promoting tumor microenvironment remodeling, the sympathetic nervous system activates β2-adrenergic receptors (ADRB2) in tumor cells and stromal cells by releasing neurotransmitters such as norepinephrine, thereby enhancing the proliferation, invasion, and metastasis of lung cancer cells [12, 72, 73]. For example, in NSCLC, sympathetic nervous system activity accelerates tumor progression by regulating M2 macrophage polarization to create an immunosuppressive microenvironment [74]. Within neuro-immune interactions, sympathetic activation recruits myeloid-derived suppressor cells (MDSCs) and inhibits T lymphocyte infiltration, leading to immune escape [75, 76]. In lung inflammation models, sympathetic excitation exacerbates macrophage-mediated inflammatory responses through adrenergic signaling, a mechanism that may similarly promote malignant progression in lung cancer [77]. Regarding neuroendocrine regulation, catecholamines released by sympathetic nerves (e.g., epinephrine) directly act on β-adrenergic receptors in lung cancer cells, activating downstream signaling pathways (e.g., cAMP/PKA) to promote tumor angiogenesis and metastasis [73, 75]. Furthermore, sympathetic denervation (e.g., local neurodegeneration) may further stimulate tumor growth by releasing neurotrophic factors such as nerve growth factor (NGF) [78]. Previous studies have found that in chemotherapy resistance, chemotherapeutic agents (such as doxorubicin) may increase the density and activity of sympathetic nerves within tumors, thereby diminishing the efficacy of chemotherapy [79]. Inhibiting sympathetic innervation (e.g., via β-blockers or chemical sympathectomy) may represent a potential strategy to enhance the therapeutic response in lung cancer [73, 80]. Notably, in a few cancers, such as pancreatic cancer, sympathetic nerves exhibit tumor-suppressive effects [81], but no similar evidence has been found in lung cancer. Existing research generally supports the pro-tumor role of sympathetic nerves [54, 81, 82].

Vagus nerve

The vagus nerve may serve as a unique pathway transmitting immune, metabolic, mechanical, and chemical signals from the tumor microenvironment to the central nervous system (CNS), thereby influencing systemic disease progression and tumor-related responses [83]. Its diverse afferent receptors (e.g., immune- and metabolism-related receptors) provide the structural basis for this bidirectional communication [84]. Concurrently, the vagus nerve modulates inflammatory responses via efferent fibers originating from the dorsal motor nucleus of the brainstem (DMN). In lung cancer, this mechanism influences the tumor microenvironment by suppressing the production of proinflammatory cytokines such as TNF-α [85, 86]. Experimental evidence from Solomiia Savchuk et al. demonstrates that vagotomy significantly inhibits the development and progression of primary tumors in SCLC, indicating that neural innervation directly promotes lung cancer growth [87]. However, in actual clinical practice, the benefits of vagotomy must be weighed against the preservation of autonomic nervous system function [88].

The vagus nerve’s interactions with the microbiome and the renin-angiotensin system (RAS) further complicate its role in cancer biology. For instance, SCLC cells may hijack neuron-activity-dependent mechanisms (such as glutamatergic and GABAergic signaling) to promote brain metastasis, suggesting the vagus nerve may regulate tumor metastasis through neurotransmitter pathways [84, 87]. Clinical studies indicate that NK-1 receptor antagonists can inhibit substance P-induced vagal nerve depolarization, providing a therapeutic target for lung cancer-related cough [89].

Extensive prior research has demonstrated that the nervous system engages in complex interactions with lung cancer cells during proliferation, invasion, and metastasis through neurons, neurotransmitters, and various neuroactive molecules [12]. NRs are not only widely expressed in cancer cells but also regulate cancer initiation and progression through multiple pathways [13] (Table 1).

Table 1.

The Effects of Neurotransmitters on Lung Cancer

Neurotransmitters	Signaling Pathways	Mechanisms of Action	Role in Lung Cancer	References
Adrenergic Agonists	cAMP/PKA pathway, MAPK pathway, ADRB2-cAMP-PKA-CREB pathway, mTOR pathway, Cdc42 signaling	Promotes cell proliferation, inhibits apoptosis, enhances epithelial-mesenchymal transition (EMT), promotes angiogenesis, enhances cell motility and invasiveness, and suppresses immunity.	Activate	[90, 99, 105]
Serotonin (5-HT)	Notch1/TAZ pathway, AMPK-dependent NLRP3 inflammasome pathway, NGF-5-HT axis	Promotes cancer cell proliferation and metastasis, upregulates PD-L1 expression to mediate immune escape; partially inhibits tumor growth and enhances T cell immunity.	Activate/inhibit	[22, 115]
Dopamine	DRD1 Receptor-Related Pathways	Downregulation of Lrp5 in tumor cells reduces expression of the proangiogenic factor CCN4; Suppression of type 2 innate lymphoid cell (ILC2) responses in lung tissue alleviates allergic pulmonary inflammation; Correlated with circulating B cell numbers, it activates B cell immune responses.	inhibit	[131]
	DRD2 Receptor-Related Pathways	Activation of MET promotes tumor stem-like cell growth; drug inhibition of DRD2 induces DRD2-TRAIL receptor interaction, triggering tumor cell death.	Activate/inhibit	[136, 137]
Glutamic Acid	Wnt-5a/PRICKLE1/REST axis, NMDAR pathway	Facilitates cystine uptake via Xc⁻ exchanger to drive glutathione biosynthesis for redox balance; activates metabotropic (mGluR1) and ionotropic (GRIN2D) receptors to promote mitogenic signaling and neuron-tumor synapse formation; promotes TAM recruitment via CCL2 secretion.	Activate	[142]
GABA	NF-κB pathway, β-catenin signaling pathway	Accumulates in NSCLC cells via ABAT suppression and FOXA2 downregulation; activates NF-κB pathway and promotes astrocyte activation to facilitate brain metastasis; inhibits GSK-3β activity via GABA receptor activation to enhance β-catenin signaling; modulates immune cell function (e.g., macrophages) within the TME.	Activate	[154–156]
Histamine	IL-6/STAT3 inflammatory signaling, JNK/p38 signaling pathways	Induce M2-like macrophage phenotype, suppress CD8+ T cell function, and influence the acidic tumor microenvironment.	Activate	[165, 166]
NPY	The specific pathway has not been identified.	Modulate immune cells in the tumor microenvironment, promote angiogenesis and inflammatory responses, and enhance neurotropism and metastasis.	Activate	[90, 175]
Acetylcholine (ACh)	GSK3β/β-catenin pathway, YTHDC1-FSP1 axis	Promote cell proliferation, migration, and metastasis; induce epithelial-mesenchymal transition (EMT); regulate immune cell function; and influence the efficacy of immunotherapy.	Activate	[190, 194]

Effects of Neurotransmitters on the development and progression of lung cancer

Adrenergic agonists

Both epinephrine and norepinephrine are catecholamine neurotransmitters. Their binding to adrenergic receptors directly promotes tumor cell proliferation and survival [90]. β-adrenergic receptors (particularly β2-AR) are overexpressed in lung cancer cells, regulating the sympathetic nervous system-mediated “fight or flight” stress response. Their activation promotes cell proliferation, inhibits apoptosis, and enhances EMT capacity through G protein-coupled receptor signaling pathways such as cAMP/PKA and MAPK pathways, thereby accelerating tumor progression [91, 92] (Fig. 2). Chronic stress promotes lung cancer growth and metastasis in preclinical mouse models by activating β-adrenergic receptor signaling through the release of catecholamines such as norepinephrine and epinephrine [93–95]. Chronic stress alters the pulmonary microenvironment, leading to increased fibronectin accumulation and neutrophil infiltration, which further suppresses T-cell function. This creates favorable conditions for metastasis, such as promoting the colonization and growth of lung cancer cells within the lungs [96].

Fig. 2.

β-Adrenergic signaling pathways in EGFR-Mutated NSCLC cells and Normal/Tumor cells. In EGFR-mutated NSCLC cells, activation of β2-adrenergic receptors induces resistance to EGFR-TKIs via an IL-6-dependent pathway. Adrenergic neurotransmitters (epinephrine and norepinephrine) bind to β-adrenergic receptors on the surface of normal tissues or tumor cells, thereby activating adenylate cyclase. This leads to transient changes in intracellular cyclic adenosine monophosphate levels. This change further activates the protein kinase A and mitogen-activated protein kinase pathways

Clinical studies indicate that β-adrenergic receptor antagonists (e.g., propranolol) can partially reverse these effects [97, 98]. In a clinical study, 16 patients with stage IIIA NSCLC received β-blockers, while 61 did not. β-blocker therapy was associated with a trend toward improved 1-year OS (81.3% vs. 57.4%, p = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, p = 0.16). In another study, olanzapine reversed chronic stress-induced anxiety-like behavior and lung cancer stemness by inhibiting the prefrontal cortex-norepinephrine-CLOCK axis. Reduced norepinephrine release prevented activation of the ADRB2-cAMP-PKA-CREB pathway, thereby suppressing CLOCK transcription and subsequently reversing lung cancer stem-like features and chemotherapy resistance under chronic stress [99].

In EGFR-mutant NSCLC cells, activation of β2-ARs promotes resistance to EGFR tyrosine kinase inhibitors (TKIs) through an IL-6-dependent mechanism [90] (Fig. 2). β2-AR signaling may also stimulate tumor growth by promoting DNA damage and inhibiting p53-associated apoptosis [100].

Research has also revealed that activation of the β-adrenergic receptor signaling pathway promotes tumor angiogenesis. This effect can be explained by mechanisms such as inducing the expression of angiogenesis-related factors like VEGF and suppressing thrombospondin-1 (TSP-1) following cAMP-response element-binding protein activation [91, 101]. Additionally, this pathway may promote tumor metastasis by enhancing cell motility and invasiveness through the enhancement of Cdc42 signaling [102]. The sympathetic neurotransmitter norepinephrine activates chemokine expression in lung cancer cells via α2-adrenergic receptors, thereby recruiting CD8 T cells into the tumor microenvironment. Disruption of sympathetic signaling leads to a reduction in these immune cells, contributing to tumorigenesis [78]. Additionally, in NSCLC patients, both cancer cells and macrophage-associated macrophages (Mo-AMs) overexpress the β 3-adrenergic receptor (ADRB3). ADRB3 supports lung cancer cell proliferation while promoting chronic inflammation and immune suppression. In mouse studies, ADRB3 was found to enhance the expansion of myeloid-derived suppressor cells (MDSCs) by stimulating bone marrow mobilization and inhibiting the differentiation of immature myeloid cells [103, 104]. Additionally, ADRB3 enhances proliferation and inhibits differentiation into adipocyte-like cells in Michigan Cancer Foundation-7 (MCF-7) cells by activating the mammalian target of rapamycin (mTOR) pathway [104]. In vitro experiments have demonstrated that M5D1, a novel anti-ADRB3 monoclonal antibody, inhibits proliferation and inflammation in human lung cancer cell lines by affecting intracellular mTOR signaling and activating p53 [105].

Perego et al. proposed that the probability of recurrence is also increased by stress. This has been supported by evidence from mouse models of lung and ovarian cancer, where experiments demonstrated that stress-activated polymorphonuclear neutrophils (PMNs) can reverse tumor cell dormancy induced by p53 gene upregulation or chemotherapy [106]. In a prospective observational STRESS-LUNG study, the relationship between emotional distress (ED) characterized by depressive and/or anxiety symptoms and the clinical efficacy of first-line ICIs in patients with advanced NSCLC was investigated. Assessment via questionnaires and scales revealed that patients with baseline ED had significantly shorter median PFS (7.9 months vs. 15.5 months, HR: 1.73, 95% CI: 1.23–2.43, P = 0.002) compared to those without ED. Exploratory analyses indicate that blood cortisol levels are elevated in the ED group. Cortisol not only induces apoptosis in T lymphocytes and neutrophils but also directly acts on tumors, thereby influencing tumor cell metastasis. This is associated with poor survival outcomes in patients [107, 108]. Persistent inflammation induces the formation of neutrophil extracellular traps (NETs), which are essential for awakening dormant cancers [109]. Mechanistic analysis indicates that two NET-associated proteases—neutrophil elastase and matrix metalloproteinase 9—sequentially cleave laminin. The proteolytically remodeled laminin induces proliferation of dormant cancer cells by activating integrin α₃β₁ signaling pathways [110].

Serotonin

Serotonin (5-hydroxytryptamine, 5-HT) is a key neurotransmitter in the central and peripheral nervous systems, involved in regulating multiple physiological functions including mood, behavior, cognition, sleep, appetite, and sexual behavior [111]. Synthesized from tryptophan, it is distributed throughout the central nervous system (e.g., the brain) and peripheral tissues (e.g., the gut, kidneys) [112, 113]. Serotonin exerts its effects through 13 distinct receptors (classified into 7 classes), which are co-expressed in multiple tissues and cell types and regulate physiological processes via complex signaling cascades [114, 115] (Fig. 3). Serotonin participates in regulating the lung cancer microenvironment, with one key mechanism being neuro-tumor signaling interactions. Lung cancer cells form a bidirectional regulatory circuit with the nervous system by secreting 5-HT. NGF drives nerve infiltration into tumor tissue, while 5-HT secreted by intratumoral nerves further promotes cancer cell proliferation and metastasis [116]. The nervous system engages in complex interactions with lung cancer cells during proliferation, invasion, and metastasis through neurons, neurotransmitters, and neuroactive molecules [12]. Additionally, serotonin mediates immune evasion by activating 5-HT receptors (5-HTR) to upregulate PD-L1 expression on tumor cell surfaces, thereby suppressing T-cell antitumor activity [115, 117]. Yang et al. demonstrated that autocrine activation of 5-HTR in tumor-infiltrating CD8 T cells enhances antitumor immunity [118]. 5-HT also influences tumorigenesis and progression by modulating inflammatory responses. For instance, 5-HT regulates inflammatory responses in lung cancer cells via the AMPK-dependent NLRP3 inflammasome pathway, and inhibiting this pathway reduces tumor malignancy [22]. Furthermore, 5-HT suppresses type II innate lymphoid cell (ILC2) activation through the HTR2A receptor, alleviating pulmonary inflammation, suggesting its dual regulatory role in lung cancer-associated inflammation [119].

Fig. 3.

The role of 5-HTR subtypes and their signaling pathways in apoptosis, proliferation, and migration of various tumor cell types.Except for 5-HTR3, which functions as a ligand-gated channel, all 5-HTRs are G protein-coupled receptors. Different 5-HT receptor families activate four major interconnected signaling pathways: the PI3K/AKT pathway, the PLC/DAG/PKC pathway, the AC-PKA-cAMP pathway, and the Ras/Raf/MAPK/ERK axis. Through these distinct signaling pathways, they drive tumor progression by promoting cancer cell proliferation, migration, and apoptosis suppression

5-HT exhibits dual tumor-promoting and tumor-suppressing effects. It promotes tumor progression through receptor-dependent pathways, such as activation of the Notch1/TAZ pathway, or via non-dependent pathways like serotoninization [120, 121]. However, research teams have discovered that inhibiting the serotonin transporter (SERT) using selective serotonin reuptake inhibitors (SSRIs)—the most widely used antidepressants—significantly suppresses tumor growth and enhances T-cell antitumor immunity in multiple mouse syngeneic and human xenograft tumor models. Importantly, SSRIs treatment demonstrated significant therapeutic synergy with programmed cell death protein 1 (PD-1) blockade [122].

Beyond the aforementioned tumor suppression pathways, small-molecule drugs targeting 5-HT receptors may modulate Tumor-Associated Macrophages (TAMs) function to reverse the immunosuppressive microenvironment [115, 123]. Experimental data indicate that the 5-HT receptor HTR2A is highly expressed on ILC2s in mouse lungs and human peripheral blood mononuclear cells (PBMCs). 5-HT improves papain-induced pulmonary inflammation by inhibiting ILC2 activation [17]. It also modulates immune cell functions (e.g., macrophage polarization, T cell activation) through different 5-HT receptor subtypes [115, 124]. Signaling pathways may also serve as potential therapeutic targets. The NGF-5-HT axis driving neural invasion and tumor progression, along with the Notch1-TAZ pathway mentioned earlier that correlates with glucose metabolism and immune evasion in lung cancer, could both become therapeutic targets [116, 120]. Inhibitors targeting the 5-HT synthase Tryptophan Hydroxylase 1 (TPH1) or the metabolic enzyme MAO can also achieve tumor suppression effects.

Dopamine

Dopamine is a catecholamine, similar to epinephrine and norepinephrine, and also serves as a precursor for their synthesis. Within the central nervous system, it regulates motor control, reward mechanisms, emotional regulation, and cognitive functions. Abnormal dopamine levels are closely associated with various neuropsychiatric disorders [125–129]. Dopamine or its receptor agonists appear to inhibit tumor growth in lung cancer and several other cancers. However, in certain experimental models, dopamine has failed to reduce tumor cell proliferation and invasion [128], suggesting that factors such as tumor type, expressed receptors, and dosage all play a role in determining the net biological effect.

One key mechanism by which dopamine inhibits lung cancer progression is through suppressing tumor angiogenesis. Studies indicate that dopamine D-receptor (DR) agonists, such as cimetidine, can significantly slow tumor progression by inhibiting angiogenesis in SCLC. This anti-angiogenic effect has been validated in multiple in vivo xenograft models and may represent a novel therapeutic strategy for chemotherapy-resistant SCLC [130]. Furthermore, in mouse brain tumor models, dopamine signaling via the DRD1 receptor downregulates low-density lipoprotein receptor-related protein 5 (Lrp5) in tumor cells, thereby reducing the expression of the proangiogenic factor CCN4 and inhibiting tumor growth [131]. The interaction between dopamine and the immune microenvironment plays a crucial role in pulmonary antitumor immunity. Dopamine suppresses the response of type 2 innate lymphoid cells (ILC2) in lung tissue via a DRD1 receptor-dependent pathway, thereby alleviating allergic pulmonary inflammation. Clinical data indicate that dopamine levels negatively correlate with ILC2 numbers and positively correlate with lung function [132]. Furthermore, dopamine activates B-cell immune responses, with plasma dopamine levels positively correlated with circulating B-cell numbers, potentially influencing antitumor immunity [133]. By inhibiting ferroptosis, dopamine modulates the endothelial cell microenvironment, promoting lung tissue regeneration rather than fibrosis—a mechanism that may contribute to lung cancer microenvironment regulation [134].

However, studies in hepatocellular carcinoma have revealed that imbalances in dopamine metabolism—such as upregulation of dopamine decarboxylase (DDC) and downregulation of monoamine oxidase A (MAOA)—can lead to increased local dopamine secretion. This, in turn, promotes tumor proliferation and metastasis via the DRD1 receptor [135]. Although this mechanism remains unconfirmed in lung cancer, it suggests that dopamine metabolism disruption may represent a common mechanism in neuro-regulated tumors.

Therefore, therapeutic targets for dopamine receptors continue to emerge. The DRD2 signaling pathway promotes glioblastoma (GBM) stem-like cells and GBM growth by activating MET. In contrast, pharmacological inhibition of DRD2 induces interaction with the DRD2-Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) receptor, triggering subsequent cell death [136, 137]. Therefore, studies have revealed the molecular regulatory network of carcinogenic DRD2 signaling: the MET receptor and TRAIL receptor act as key factors for tumor cell survival and cell death, respectively, jointly regulating survival and death in glioblastoma. In lung cancer treatment, DRD2 inhibitors (such as ONC201) have entered clinical trial phases [136]. Dopamine pretreatment attenuates the efficacy of anticancer drugs (e.g., ONC201/ONC206) against pancreatic and colorectal cancers, suggesting that dopamine signaling pathways may be implicated in chemotherapy resistance [136, 138].

Glutamic acid

Glutamate exerts its effects on lung cancer development through multiple neuromodulatory mechanisms. Regarding oxidative stress regulation, lung cancer cells actively uptake glutamate via transporters such as the sodium-dependent transporter (SLC1A1), facilitating cystine entry through the Xc⁻ exchanger and thereby driving glutathione (GSH) biosynthesis [139–141]. This process is crucial for maintaining redox balance in lung cancer cells. Deficiency of SLC1A1 leads to extracellular glutamate accumulation, inhibits cystine uptake, blocks GSH synthesis, and ultimately triggers oxidative stress-mediated cell death or growth suppression. Furthermore, glutamate transporters such as excitatory amino acid transporter 3 (EAAT3) are frequently upregulated in NSCLC tissues, further supporting the critical role of glutamate metabolism in tumorigenesis [142].

Glutamate promotes tumor progression by activating metabotropic (mGluRs) and ionotropic (iGluRs) receptors. The metabotropic receptor mGluR1 is induced in the brain microenvironment by astrocytes via the Wnt-5a/PRICKLE1/REST axis, interacting with Homer3 to activate downstream mitogenic signaling [143]. The ionotropic receptor GRIN2D functions at neuron-tumor pseudosynapses, enabling tumor cells to respond to glutamate released by neurons, thereby promoting growth and dissemination [144]. Activation of glutamate receptors also phosphorylates sarcoma-associated signaling molecules, further driving tumor progression [145].

Astrocytes promote tumorigenesis and progression by altering glutamate homeostasis [146]. Glutamate downregulates miR-22 expression via the NMDAR pathway, thereby promoting CCL2 secretion and recruiting TAMs [145]. Glutamate accumulation in the tumor microenvironment decouples neuronal calcium signaling, establishing a unique excitatory homeostasis pattern [147]. These pathways collectively influence tumorigenesis and progression by modulating the tumor microenvironment.

Therefore, targeting glutamate transporters (such as SLC1A1, EAAT3) or Xc⁻ exchangers can interfere with GSH synthesis [139], thereby enhancing oxidative stress. Inhibiting glutamate receptors (such as mGluR1, NMDA receptors) or blocking neuron-tumor interactions (such as GRIN2D antagonists) may suppress tumor growth [144, 147, 148]. Preclinical models have demonstrated that disrupting glutamate signaling pathways using AMPA receptor inhibitors improves prognosis in animal studies [147, 149], although this strategy has not yet been translated to clinical settings.

Gamma-Aminobutyric Acid (GABA)

GABA is the primary inhibitory neurotransmitter in the vertebrate central nervous system (CNS), exerting a sedative effect by reducing neuronal excitability and regulate synaptic transmission and neuronal development [150–153]. Recent studies have revealed significantly elevated GABA levels in both cells and serum of NSCLC patients with brain metastases, suggesting GABA plays a pivotal role in NSCLC brain metastasis. Tumor cells suppress 4-aminobutyric acid aminotransferase (ABAT) by downregulating forkhead box protein A2 (FOXA2) expression, leading to GABA accumulation. GABA subsequently activates the NF-κB pathway and astrocytes, thereby promoting brain metastasis of NSCLC [154]. Lung cancer cell-derived IL-13 activates STAT6 signaling in the choroid plexus, thereby upregulating the GABA synthase GAD67 and the GABA permeability channel Bestrophin-1. This increases GABA levels in cerebrospinal fluid, further promoting brain metastasis [155].

GABA also promotes tumor cell proliferation and immune suppression by regulating the tumor microenvironment. For instance, GABA inhibits GSK-3β activity via GABA receptor activation, thereby enhancing β-catenin signaling [156]. GABA also modulates the function of immune cells (e.g., macrophages) within the tumor microenvironment. For instance, GABA-induced tumors influence macrophage distribution and activity via exosomes [157]. Concurrently, the GABAergic system modulates neural circuit activation through GABA receptors and GABA transporters (GAT), influencing neuro-immune interactions within the tumor microenvironment [158, 159]. Modulation of the GABAergic system may emerge as a novel therapeutic target for lung cancer. For example, targeting GABA synthases (such as GAD67) or GABA receptors (such as GABA-A receptors) may inhibit tumor progression and metastasis [160]. When co-cultured with neurons, lung cancer cells express classical neurotransmitter receptor genes (e.g., HTR4, GRIA2, GRIN2B) and synaptic mediators (e.g., CNR1, EGR2), indicating that GABAergic signaling plays a crucial role in neuro-tumor interactions [156, 161]. In brain metastases of breast and lung cancers, tumor cells transition from relying on autocrine GABA to depending on paracrine GABA from neurons, representing a key early adaptation strategy within the central nervous system [154, 161].

Histamine

Histamine is a biologically active amine with significant physiological and pathological functions, most notably for triggering allergic reactions. Four G protein-coupled histamine receptor subtypes mediate the actions of histamine in neurons [162, 163]. Histamine receptor H3 (HRH3) shows significantly upregulated expression in NSCLC, and its high expression correlates with poorer patient OS, with an HR of 1.16 and a P value of 0.022 [164]. Histamine receptor H1 (HRH1) is overexpressed in various cancers, including lung cancer. Activation of HRH1 induces an M2-like phenotype via TAMs and upregulates the immune checkpoint molecule VISTA, thereby suppressing CD8 + T cell function and leading to resistance to immunotherapy [165, 166] (Fig. 4). In neuroinflammatory contexts, histamine indirectly modulates the immune state of the tumor microenvironment by activating microglia (immune cells of the central nervous system) to release cytokines such as IL-10 [167, 168]. A similar mechanism may underlie neuro-regulation in lung cancer.

Fig. 4.

The role of antihistamines in TAM polarization regulation, CD8⁺ T cell function modulation, and the efficacy of immune checkpoint inhibition therapy. TAMs are the primary cells expressing H1R in tumor tissues. Upon activation, H1R induces a series of effects on TAMs: reshaping their gene expression profiles toward an M2-like phenotype, inducing intracellular calcium release, upregulating the expression of surface inhibitory molecules, and simultaneously promoting TAM differentiation toward M2-like macrophages. During this process, the antitumor activity of TAMs alternates between enhancement and suppression. Additionally, H1R activation exerts subsequent effects through specific mechanisms: it suppresses CD8 + T cell function, reducing IFN-γ and perforin-1 production; simultaneously, it mediates these actions by binding VISTA to the T cell surface receptor P-selectin glycoprotein ligand-1

Clinical data indicate that elevated plasma histamine levels correlate with reduced response rates to PD-1 inhibitor therapy in cancer patients. Patients with low histamine levels exhibit objective response rates more than three times higher than those with high levels [165]. Sufentanil inhibits tumor growth by blocking HRH1, reducing MDSCs infiltration, and suppressing IL6/STAT3 inflammatory signaling [169]. This finding supports antihistamines as a potential adjuvant to immunotherapy in lung cancer. However, histamine signaling can influence the acidic microenvironment of lung cancer cells by regulating the localization and internalization of carbonic anhydrase 12 (CA12). As a carcinogenic factor, histamine-mediated CA12 internalization may inhibit tumor growth [170, 171].

Research has also revealed that loratadine can activate PP2A and inhibit STAT3, JNK, and p38 signaling pathways through non-HRH1-dependent mechanisms, thereby inducing autophagy-mediated apoptosis. It has demonstrated antitumor effects in both in vitro cell experiments and in vivo xenograft models. Furthermore, lung adenocarcinoma patients with high PP2A expression exhibit better prognosis [172]. Kaplan-Meier survival analysis revealed that among lung cancer patients receiving anti-PD-1/PD-L1 therapy, those treated with H1-antihistamines demonstrated significantly longer OS compared to those not receiving this class of drugs [165]. Although histamine typically promotes immunosuppression via HRH1, its effect on CA12 internalization may be independent of immunoregulation, directly inhibiting tumor cell survival through acidification stress. This provides theoretical support for the “histamine-CA12 axis” as a therapeutic target [166, 170].

Neuropeptide Y (NPY)

NPY receptors are overexpressed in various cancers. NPY exerts its effects through G protein-coupled receptors (Y1R, Y2R, Y5R), which activate multiple signaling pathways regulating cell growth, differentiation, apoptosis, proliferation, angiogenesis, and metabolism [173]. These functions are closely linked to tumor biology, including sustained proliferative potential, resistance to cell death, angiogenesis, invasion, and metastasis. Expression levels of different NPY receptor subtypes vary between tumor and normal tissues, making them potential molecular targets for cancer diagnosis and treatment [174]. Although a systematic roadmap for developing anti-cancer drugs targeting NPY receptors is currently lacking, the characterization of NPY receptor subtypes and their distribution across different cancers offers new insights for targeted therapy in lung cancer [175]. The NPY system not only participates in the regulation of energy homeostasis but also promotes tumorigenesis in various cancers. For example, in pancreatic cancer, NPY expression correlates with tumor progression. Similar mechanisms may be at play in lung cancer, although the specific role requires further investigation [90, 176]. As a sympathetic neurotransmitter, NPY may influence lung cancer progression by regulating immune cells, angiogenesis, and inflammatory responses within the tumor microenvironment [177]. As a prototypical neuroendocrine tumor, SCLC may form bidirectional regulatory circuits with the nervous system through neuropeptide secretion (e.g., NPY), thereby promoting tumor neurotropism and metastasis [54, 178].

The expression levels of NPY and its receptors may serve as diagnostic or prognostic markers for lung cancer [179]. Targeting the NPY signaling pathway—particularly when combined with other therapeutic strategies—may significantly enhance treatment outcomes for lung cancer, especially in subtypes exhibiting pronounced neuroendocrine characteristics [180, 181].

Acetylcholine (ACh)

ACh functions as a neurotransmitter in the nervous system, acting at sites including: autonomic ganglia, organs innervated by the parasympathetic nervous system, and the neuromuscular junction between motor nerves and skeletal muscles. Acetylcholine receptors (AChRs) are classified into two types: relatively slow-activating G protein-coupled metabolic acetylcholine receptors (mAChRs) and faster-activating ionotropic nicotinic acetylcholine receptors (nAChRs). Acetylcholine contributes to the regulation of cellular proliferation, differentiation, and apoptosis processes [182–186].

It is well known that ACh signaling attenuation is associated with diseases such as myasthenia gravis (MG) [187]. Recent studies have revealed that ACh plays multifaceted key roles in the neuromodulation of lung cancer, with its mechanisms involving tumor microenvironment regulation, immune modulation, and tumor progression. Acetylcholine directly promotes the proliferation, migration, and metastasis of lung cancer cells by binding to nAChRs and mAChRs. As a calcium channel, the α7 nAChR plays a crucial role in lung cancer proliferation, chemotherapy resistance, and metastasis, with its molecular mechanisms elucidated in preclinical studies [188]. Genome-wide association studies indicate that CHRNA5, encoding the α5-nicotinic acetylcholine receptor (α5-nAChR), is associated with elevated PD-L1 expression in smoking-related lung cancer, potentially influencing immunotherapy response [42]. In in vitro studies using lung adenocarcinoma cell lines, allosteric modulators of nicotinic acetylcholine receptors (such as spinosad) have been shown to significantly inhibit cancer cell proliferation by suppressing receptor activity [189], although clinical evaluation of this approach has not yet been conducted.

Beyond directly influencing lung cancer progression through receptors, Ach also affects tumor development via neuro-tumor microenvironment interactions. Ach, secreted by tumor-infiltrating nerves or cancer cells themselves, promotes metastasis by inducing EMT. For instance, in cholangiocarcinoma, the ACh/CHRNA5 axis drives metastasis by activating the GSK3β/β-catenin signaling pathway [190]. Chronic stress (such as restraint stress) increases ACh levels, promoting the growth and metastasis of lung adenocarcinoma cells [191]. ACh also influences the tumor microenvironment by regulating immune cell function. It not only directly modulates innate and adaptive immune responses—such as through neuro-immune interactions with type 2 innate lymphoid cells (ILC2) that may affect immune escape in lung cancer [192, 193]—but may also impact the efficacy of immunotherapy by influencing immune checkpoint molecules [42]. Ach also influences tumorigenesis and progression through cross-regulation with other signaling pathways. Reports indicate that IL-33 is closely associated with lung cancer progression and exerts opposing effects on lung cancer under different conditions. ACh may participate in the immunoregulatory and fibrotic processes of lung cancer via neuroactive molecules such as IL-33 [17]. Furthermore, the ACh/CHRNA5 axis promotes tumor metastasis by activating the GSK3 β/β-catenin pathway [10], and ACh-related signaling may indirectly influence ferroptosis sensitivity in lung cancer cells via the YTHDC1-FSP1 axis [194] (Fig. 5).

Fig. 5.

Nicotine Modulates the α5-nAChR/START3/Jab1 Signaling Axis to Upregulate PD-L1 to Promote Tumor Immune Evasion After nicotine activates the α5-nAChR on cancer cells, it regulates the post-translational modification of START3, enabling it to form a complex with Jab1 and drive the transcriptional upregulation of PD-L1. The interaction between PD-L1 and PD-1 on T cells and NK cells induces multiple immunosuppressive effects: first, it promotes T cell functional tolerance and drives the expansion of Tregs with an immunosuppressive phenotype; second, it inhibits IFN-γ and IL-2 secretion by CTLs and granzyme B release by NK cells, thereby weakening their cytotoxic activity

β-blockers

If adrenergic agonists promote lung cancer progression by activating β-adrenergic receptor signaling through the release of catecholamines such as norepinephrine and epinephrine, thereby enhancing tumor growth and metastasis [93, 94, 195], then whether inhibiting this activation could provide clinical anticancer benefits has become a research hotspot in the field of tumor neuromodulation, particularly given the readily available β-blocker drugs [196, 197]. β-blockers are primarily used to treat arrhythmias and hypertension [198–200]. They act as competitive antagonists that block the receptor sites for epinephrine and norepinephrine on adrenergic β receptors [201]. Emerging evidence suggests that β-blockers may also possess anticancer effects and contribute to overcoming drug resistance in cancer therapy [91, 202, 203]. Currently, the role of β-blockers in lung cancer treatment has garnered attention in multiple studies.

The antitumor mechanisms of β-blockers are primarily achieved through several pathways. First, the sympathetic nervous system can accelerate tumor progression by promoting tumor microenvironment remodeling and releasing neurotrophic factors (as described earlier). β-blockers directly antagonize β-adrenergic receptors (particularly β−2 adrenergic receptors), thereby reducing sympathetic nervous system activity and inhibiting tumor cell proliferation, angiogenesis, and metastasis [197, 202]. Second, non-selective β-blockers (such as propranolol) may enhance the efficacy of ICIs by inhibiting stress-induced immunosuppression [204, 205]. Clinical observations indicate that combining β-blockers with ICIs improves objective response rates (ORR), particularly in NSCLC patients. Among 200 eligible patients, 53 (27%) received β-blocker pretreatment. Compared to the non-β-blocker group, patients pretreated with β-blockers demonstrated significantly improved median OS (12 months vs. 24 months, p = 0.004) and PFS (6 months vs. 8 months, p < 0.001). In NSCLC patients receiving pembrolizumab, baseline β-blocker use demonstrated a strong and independent association with improved OS and PFS [204]. Additionally, β-blockers modulate apoptosis pathways and cancer stem cell activity by inhibiting antioxidant stress pathways (such as SOD-2) and pro-survival signaling (such as AKT/mTOR) downstream of β−2 adrenergic receptors (β2-AR) [206], thereby enhancing chemotherapy sensitivity and reversing chemotherapy resistance [202]. The non-selective β-blocker carvedilol (CAR) reduces cell viability in A549 and H1299 cells by affecting a novel target called aldehyde dehydrogenase (ALDH). Compared to the control group, CAR caused a 50% decrease in ALDH expression and an 80% reduction in ALDH activity in A549 cells, particularly when combined with β-agonists [207].

In terms of clinical efficacy, β-blockers have also demonstrated certain advances. Firstly, as adjuvant therapy, β-blockers can prolong OS and recurrence-free survival (RFS) in NSCLC patients while reducing the incidence of metastasis [208]. For patients with unresectable NSCLC and concomitant cardiovascular disease (CVD), the use of β-blockers and statins following sequential chemoradiotherapy increases OS from 33.4% to 42.9% [209, 210]. In NSCLC patients with hypertension undergoing radiotherapy, β-blockers may provide cardioprotection and prolong OS. In a Chinese clinical cohort, β-adrenergic blockade was associated with improved OS (β-adrenergic blockade group: mOS 17.64 months, 95% CI 15.95–19.33; non-β-adrenergic blocker group: mOS 13.16 months, 95% CI: 12.62–13.70; P < 0.0001) [211]. Second, perioperative use of β-blockers may improve postoperative outcomes in lung cancer by blocking adrenergic responses [212]. Preclinical studies suggest that β-blockers may reduce pulmonary infiltration of circulating tumor cells (CTCs) by inhibiting tumor cell transendothelial migration (e.g., MBFD drug model), though their use has no significant effect on CTC clearance rates [213–215]. Currently, the benefits of β-blockers on DFS and OS in epidemiological or perioperative settings remain variable, tumor-specific, and supported by low-level evidence [216].

However, current research also exhibits certain controversies and limitations. For instance, some studies failed to identify a significant association between β-blockers and lung cancer prognosis [217], and official β-blockers did not improve RFS or OS in resected NSCLC patients [218]. Furthermore, a Portuguese study demonstrated that combining β-blockers with ICIs did not significantly increase survival benefits [219]. Due to receptor subtype differences, β1-selective blockers (e.g., bisoprolol) may act differently from non-selective blockers. Current evidence more strongly supports the anticancer effects of non-selective agents [80, 204]. Existing evidence primarily stems from retrospective studies or small-scale clinical trials, necessitating large-scale randomized controlled trials to clarify optimal dosing regimens and target populations [220].

α2-Adrenergic receptor agonists

Although the mechanism of action of β-adrenergic receptors has received greater attention, other adrenergic receptors also appear to be relevant. α2-adrenergic receptor agonists (such as dexmedetomidine, DEX) have demonstrated significant antitumor activity in multiple immunologically active tumor models, particularly in models resistant to ICIs [221]. This effect depends on immune system involvement, as no similar effect was observed in immunodeficient models [222]. Experiments also demonstrated significant antitumor effects in tumor xenograft models transplanted into mice reconstituted with human lymphocytes. The antitumor activity of α2-AR agonists was reversed by α2-AR antagonists [222]. Furthermore, its efficacy may be influenced by dosage, immune cell type, and combination with other immunotherapies [221]. Certain α2-adrenergic receptor agonists (e.g., epinephrine) may simultaneously act on other adrenergic receptors (e.g., β-adrenergic receptors), leading to complex biological effects. For instance, epinephrine exhibits antitumor activity when β-adrenergic receptors are blocked, but may promote tumor growth when β-adrenergic receptors are activated [223].

Some studies suggest that adrenergic signaling (including α2-adrenergic receptor activation) may promote tumor progression under certain conditions, such as by inducing tumor cell proliferation or immunosuppression [224]. Research by Szpunar et al. demonstrated that treatment with dexmedetomidine, a highly selective α2-adrenergic receptor agonist, promoted tumor growth and metastasis in mice [225]. Dexmedetomidine is a commonly used surgical anesthetic. Based on in vitro and xenograft in vivo experiments, Xia et al. reported that dexmedetomidine promotes proliferation, migration, and invasion of breast cancer cells by activating the α2B-adrenergic receptor/ERK signaling pathway [226, 227].

Neurotransmitter signaling pathways may influence the efficacy of ICIs. For example, certain neurotransmitters can induce resistance through mechanisms beyond PD-1/PD-L1 or CTLA-4 pathways, such as inflammatory responses or immune cell function [228]. Targeting these pathways may enhance antitumor effects [229]. Existing neurotransmitter-related drugs (e.g., antidepressants or antipsychotics) may be repurposed for NSCLC treatment through “old drugs, new uses” strategies. For instance, drugs targeting serotonin or adrenergic receptors have demonstrated antitumor potential in breast cancer, and similar mechanisms may apply to NSCLC [10, 201, 230–233] (Table 2). Further research is needed to define specific targets and regulatory networks of neurotransmitters in NSCLC. For example, elucidating the role of GABAergic signaling in brain metastasis [154] or developing novel combination therapies targeting neuro-immune crosstalk in the tumor microenvironment [12, 64]. Additionally, optimizing drug delivery systems to enhance targeting and reduce toxicity is essential [234].

Table 2.

Neurotherapeutic Strategies for Lung Cancer

Therapy type	Drug	Treatment Pathway	Clinical Status	references
Beta-blockers	Propranolol	Beta-adrenergic signaling, reduces tumor growth	NCT00409968 NCT00949650	[204, 205]
α2-Adrenergic receptor agonists	Prazosin	Increases oxidative stress, reduces tumor viability	/	[221, 222]
Dopamine receptor antagonist	Quetiapine	Inactivates ERK/AKT pathways, induces apoptosis	/	[136, 138]
Partial agonist of acetylcholine receptors	cytisine	Preventing lung cancer through smoking cessation therapy	NCT03654105	[233]
Acetylcholine receptor antagonist	Dafinacin	By blocking the YAP-ChAT-ACh-M3R-WNT signaling axis to reverse EGFR-TKI resistance	/	[190]
Glutamate receptor antagonist	Memantine	Inhibit tumor growth	/	[180, 181]
SSRI	Fluoxetine	Inhibits ERK/NF-κB signaling, induces apoptosis	NCT00005850	[122]
SNRI	Duloxetine	Enhances caspase activity, induces apoptosis	/	[231]
Thymosin	Thymalfasin	Monotherapy + Combination Therapy. Inhibition of the STAT3/MMP2 pathway.	/	[230]
TMEM16A inhibitor	cryptochlorogenic acid(CCA)	Inhibiting TMEM16A ion channel activity to regulate MAPK and EMT pathways	/	[232]

Mechanisms of neurotransmitter-tumor microenvironment interactions

Neurotransmitters influence antitumor immune responses by modulating immune cell functions within the tumor microenvironment. Studies have revealed that tumor-infiltrating immune cells—including T cells, B cells, macrophages, myeloid-derived suppressor cells, and dendritic cells—express multiple neurotransmitter receptors. Activation of these receptors may either enhance or suppress immune activity [14, 235]. Neurotransmitters may influence immune evasion by modulating immune checkpoint molecules. For instance, increased PD-1-positive T cells and reduced immune cells correlate with an immunosuppressive microenvironment in lung cancer brain metastases [92]. TAMs constitute a major component of the lung cancer microenvironment, promoting tumor growth and metastasis by secreting pro-tumor factors (such as angiogenesis factors) and suppressing T cell function [123, 236]. Neurotransmitters may influence the microenvironment by regulating the polarization state of TAMs (e.g., pro-inflammatory M1 or anti-inflammatory M2 types) [235]. Neurotransmitters (such as catecholamines and serotonin) and neuropeptides regulate the dynamic equilibrium of the tumor microenvironment through neuroendocrine axes. For instance, psychostress-induced neurotransmitters (e.g., norepinephrine) activate immunosuppressive pathways via β-adrenergic receptors, thereby promoting tumor progression [16, 230]. Lung cancer cells themselves can also secrete neurotransmitters, influencing surrounding cells such as endothelial cells and fibroblasts through autocrine or paracrine actions to promote inflammation and angiogenesis [15].

Therefore, modulating neurotransmitter-immune cell interactions by enhancing NK cell function or reversing T cell exhaustion may overcome ICIs resistance [237]. Furthermore, gut microbiota-derived neurotransmitters influence lung cancer progression through immunomodulation, offering novel insights for combination therapies [229, 238]. Neurotransmitters produced by gut microbiota—such as 5-HT, dopamine, GABA, and glutamate—can affect peripheral and central nervous systems via the gut-brain axis (GBA), thereby regulating immune cell function within the TME [239]. Dysbiosis may elevate levels of pro-inflammatory neurotransmitters such as glutamate, thereby activating TAMs and inhibitory T cells to form an immunosuppressive microenvironment [240]. Conversely, certain probiotics may enhance responses to anti-PD-1/PD-L1 immunotherapy by producing inhibitory neurotransmitters like GABA [16, 241]. These findings offer new insights into the neuro-immune cross-regulation in lung cancer and establish a theoretical foundation for developing combined therapies targeting the microbiome and neurotransmitters [242].

Biomarker

Potential of neurotransmitter receptors in lung cancer diagnosis

The nervous system engages in complex interactions with lung cancer cells through neurons, neurotransmitters, and neuroactive molecules, participating in tumor proliferation, invasion, and metastasis processes [12]. Neurotransmitter receptors (NRs) are not only widely expressed in lung cancer cells but also regulate tumor development through multiple pathways, making them potential diagnostic biomarkers [13]. Abnormal expression of different NRs subtypes in lung cancer tissues can distinguish between lung cancer subtypes and benign/malignant lesions [243]. For example, α7 and α5 nAChRs are highly expressed in lung cancer and are closely associated with the development of tobacco-related lung cancer, serving as auxiliary diagnostic indicators for this type of lung cancer [188, 189]. GABA may play a significant role in NSCLC brain metastasis, while the high expression of neurokinin-1 receptors (NK1R) in lung cancer tissues suggests its potential as a diagnostic or prognostic marker [154, 243]. Combined detection of NRs with traditional tumor markers can enhance the sensitivity and specificity of lung cancer diagnosis. For example, the neurotropic enolase (NSE), as a neuroendocrine tumor marker, when co-detected with 5-HTRs, can assist in the diagnosis and differentiation of SCLC [165–168]. Combined detection of serum NRs-related molecules (such as neuropeptide Y receptors and dopamine receptors) with carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) aids in the early screening of lung cancer [12, 13]. NRs can influence lung cancer progression by modulating immune cell activity within the tumor microenvironment (e.g., promoting antitumor immune responses) [14]. For instance, targeting specific receptors (such as dopamine or 5-HTRs) may enhance immunotherapy efficacy [229]. Additionally, literature suggests that expression patterns of different NRs subtypes in lung cancer may exhibit tissue specificity. For instance, certain receptor subtypes are highly expressed in neuroendocrine-like lung cancers (e.g., SCLC) and may serve as molecular markers for subtyping [178].

However, existing literature primarily focuses on the mechanisms of NRs in lung cancer biology, with few specific cases directly addressing diagnostic applications. Future research should clarify the diagnostic sensitivity and specificity of specific receptors [243].

The potential of NRs in lung cancer prognosis

The expression of certain NRs is associated with the regulation of the tumor immune microenvironment and may serve as prognostic biomarkers for lung cancer [15, 228]. For example, overexpression of the CASZ1 gene is significantly associated with lung cancer metastasis and poor prognosis, suggesting that neurotransmitter-related pathways may influence lung cancer progression through mechanisms such as EMT [244]. Furthermore, studies on colorectal cancer indicate that abnormal activation of neurotransmitter signaling pathways (e.g., acetylcholine receptors) may accelerate disease progression by promoting inflammation and angiogenesis. Similar mechanisms may underlie lung cancer development [15].

However, the specific mechanisms of NRs in lung cancer require further investigation, particularly their association with immune therapy resistance [245]. In summary, NRs hold significant potential in prognosis assessment and therapeutic target development by regulating the biological behavior, immune microenvironment, and stress responses of lung cancer. Nevertheless, additional research is needed to validate their clinical translational value.

The relationship between radiomics and NRs

Radiomics enables non-invasive characterization of tumor heterogeneity by quantifying imaging features such as texture and shape, and has been explored for predicting immunotherapy response [246–248]. Multiple studies have attempted to correlate CT/PET radiomics features with receptor mutation status, particularly EGFR. For example, the Subregion Radiomics Model (SRRM) has been shown to predict response to EGFR-TKI therapy, suggesting that imaging features may indirectly reflect receptor expression or mutation status [249, 250]. Additionally, integrating PET/CT radiomics with glucose metabolism-related genomic features may reveal cross-regulatory interactions between metabolic pathways and receptor signaling within heterogeneous tumor regions [251]. However, direct evidence linking NRs expression to specific radiomics features remains scarce; existing studies primarily rely on indirect pathway analyses, and whether radiomics can specifically map to the spatial distribution of particular receptors (e.g., 5-HTRs family or opioid receptors) requires further validation [252, 253].

Challenges and future directions

Research bottlenecks in studying neurotransmitter concentration gradient effects

A major technical challenge is the dynamic concentration gradient distribution of neurotransmitters within the tumor microenvironment, which significantly influences receptor activation thresholds in a spatially heterogeneous manner [254]. This spatial heterogeneity makes it difficult for in vitro results to accurately reflect in vivo conditions. For example, NMDA receptors exhibit specific expression patterns in NSCLC, yet the subcellular localization and functional regulation of their subtypes remain unclear [255]. The development of more precise in vivo concentration monitoring techniques is urgently needed to address this bottleneck, as current methodologies are inadequate for capturing real-time neurotransmitter dynamics at the single-cell or sub-regional level within tumors [256].

Challenges in developing receptor subtype-specific drugs

NRs subtypes exhibit complex biological functional heterogeneity in lung cancer. EGFR mutation subtypes demonstrate distinct clinical manifestations and therapeutic responses among lung cancer patients [257], providing important insights for developing NRs subtype-specific drugs. Research confirms that the ERβ5 subtype exhibits unique interactions with IL-6R during lung cancer progression [258], while muscarinic receptors within the cholinergic receptor family demonstrate antitumor effects in drug screening as potential therapeutic targets [259]. However, the high homology and cross-activation properties among receptor subtypes pose significant challenges for selective drug design [13], necessitating breakthroughs through integrated structural biology and computational chemistry approaches. Furthermore, neuromodulation exhibits bidirectional effects—for instance, IL-33 and many neurotransmitters mentioned earlier can both promote tumor growth and enhance antitumor immunity in lung cancer, demanding precise regulation [17].

Clinical translation challenges and technical bottlenecks

The safety and efficacy of neuromodulatory therapies such as bispecific antibodies (bsAbs) in lung cancer still require large-scale validation [260]. Convolutional neural networks (CNNs) not only identify malignant pulmonary nodules but also demonstrate high accuracy in directly classifying lung cancer histological types/subtypes from CT data. Scan-based 3D CNNs such as 3D ResNet50 and Hierarchical Semantic 3D CNNs can adapt to the 3D volumetric imaging data of neuro-oncological tumors, preserving spatial structural information and enhancing classification accuracy. However, CNN applications still face challenges, including insufficient annotated data, poor reproducibility, and low interpretability of results [261]. Dynamic monitoring of neuro-tumor interactions requires in vivo imaging techniques with higher spatiotemporal resolution [262]. Therefore, during clinical translation, it is essential to first elucidate the biological mechanisms underlying cancer-neuron interactions, extract relevant molecular mediators from human samples, and conduct research using preclinical models. When designing clinical trials, consideration must be given to potential neurological side effects of drugs, and non-pharmacological treatment approaches such as neuromodulation should be explored [263].

Optimization and innovation of research models

Current in vitro studies often co-culture neurons solely with cancer cells, lacking other key cells of the tumor microenvironment. Future research should establish complex models incorporating glial cells, immune cells, cancer-associated fibroblasts, and others. Utilizing 3D tumor organoid culture systems and adding tumor extracellular matrix components—such as specific collagen subtypes and growth factors—can simulate the in vivo environment, thereby more precisely elucidating the mechanisms of neuro-cancer interactions [264]. Current mouse models (such as KRAS-based pancreatic cancer models) struggle to fully replicate the neuroinvasive characteristics of human cancers. Future efforts should prioritize developing mouse models that more closely mimic human disease, for example by utilizing neuropathological features of human cancers - molecular markers of neuroplasticity in human cancers; simultaneously exploring alternative species models like pigs (due to their greater anatomical, size, and physiological similarity to humans), and validating the capacity of patient-derived xenografts (PDXs) to induce neurogenesis and neuroinvasion in mouse models [263, 265].

Translational research pathways for multi-omics integration Analysis

Multi-omics integrated analysis offers a systems-level perspective for deciphering neurotransmitter regulatory networks. Radiomics has already achieved classification of lung cancer histological subtypes and EGFR mutation status [15], providing a methodological foundation for establishing neurotransmitter receptor expression profiles. Similarly, network analyses of glycosphingolipids have revealed subtype-specific molecular variations [266], suggesting that analogous approaches for neurotransmitter pathways may uncover novel therapeutic targets. Future research should integrate PET/CT radiomics, single-cell sequencing, and spatial transcriptomics data to construct comprehensive regulatory maps of neurotransmitter-tumor interactions, enabling more precise patient stratification and personalized therapeutic strategies [267].

Conclusion

In conclusion, the nervous system exerts a significant influence on the pathogenesis and prognosis of lung cancer, profoundly shaping tumor progression through psychological factors, sleep disorders, neurotransmitter signaling, immune regulation, and metabolic control. This review systematically reveals how specific neurotransmitters drive key molecular pathways, thereby exerting dual regulatory effects on tumor growth, metastasis, immune evasion, and chemotherapy resistance. In-depth exploration of the roles of the central and peripheral nervous systems in tumorigenesis and metastasis provides robust evidence for potential clinical translation. It highlights neurogenic biomarkers and their prognostic relevance, further underscoring the potential importance of neuroimmunotherapy in cancer treatment—although it must be acknowledged that most of these therapeutic strategies remain at the preclinical stage, and only a limited number, such as β-blockers and H1-antihistamines, have preliminary retrospective clinical evidence supporting their use. This integrated neuroscience perspective not only represents an innovative frontier in lung cancer research but also lays a promising foundation for future clinical advancements.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

5-HT

5-Hydroxytryptamine

5-HTR

5-Hydroxytryptamine Receptor

ACh

Acetylcholine

AChR

Acetylcholine Receptor

ADRB2

Beta-2 Adrenergic Receptor

ADRB3

Beta-3 Adrenergic Receptor

AI

Artificial Intelligence

ALDH

Aldehyde Dehydrogenase

AMPK

AMP-activated Protein Kinase

AR

Adrenergic Receptor

bsAbs

Bispecific Antibodies

CA12

Carbonic Anhydrase 12

CAR

Carvedilol

CASZ1

Castor Zinc Finger 1

CCL2

C-C Motif Chemokine Ligand 2

CD8

Cluster of Differentiation 8

CEA

Carcinoembryonic Antigen

CHRNA5

Cholinergic Receptor Nicotinic Alpha 5 Subunit

CI

Confidence Interval

CLOCK

Circadian Locomotor Output Cycles Kaput

CNNs

Convolutional Neural Networks

CNS

Central Nervous System

CPT1A

Carnitine Palmitoyltransferase 1 A

CREB

cAMP Response Element-Binding Protein

CTCs

Circulating Tumor Cells

CTLA-4

Cytotoxic T-Lymphocyte-Associated Protein 4

CVD

Cardiovascular Disease

CXCL

C-X-C Motif Chemokine Ligand

CYFRA21-1

Cytokeratin 19 Fragment

DDC

Dopamine Decarboxylase

DEX

Dexmedetomidine

DFS

Disease-Free Survival

DMFS

Distant Metastasis-Free Survival

DMN

Dorsal Motor Nucleus

DNA

Deoxyribonucleic Acid

DR

Dopamine Receptor

DRD1

Dopamine Receptor D1

DRD2

Dopamine Receptor D2

EAAT3

Excitatory Amino Acid Transporter 3

ED

Emotional Distress

EGFR

Epidermal Growth Factor Receptor

EMT

Epithelial-Mesenchymal Transition

ERK

Extracellular Signal-Regulated Kinases

FOXA2

Forkhead Box Protein A2

GABA

Gamma-Aminobutyric Acid

GBA

Gut-Brain Axis

GBM

Glioblastoma

GSH

Glutathione

GSK3β

Glycogen Synthase Kinase 3 Beta

HIF-1α

Hypoxia-Inducible Factor 1-Alpha

HPA

Hypothalamic-Pituitary-Adrenal

HR

Hazard Ratio

HRH1

Histamine Receptor H1

HRH3

Histamine Receptor H3

ICIs

Immune Checkpoint Inhibitors

IFN-γ

Interferon Gamma

MAO

Monoamine Oxidase

MAOA

Monoamine Oxidase A

MAPK

Mitogen-Activated Protein Kinase

MCF-7

Michigan Cancer Foundation-7

MDSCs

Myeloid-Derived Suppressor Cells

MET

Mesenchymal-Epithelial Transition Factor

MG

Myasthenia Gravis

mGluRs

Metabotropic Glutamate Receptors

miRNAs

MicroRNAs

mTOR

Mammalian Target of Rapamycin

nAChRs

Nicotinic Acetylcholine Receptors

NETS

Neutrophil Extracellular Traps

NGF

Nerve Growth Factor

NK

Natural Killer cells

NK1R

Neurokinin-1 Receptor

NLRP3

NLR Family Pyrin Domain Containing 3

NMDA

N-Methyl-D-Aspartate

NMDAR

N-Methyl-D-Aspartate Receptor

NPY

Neuropeptide Y

NRs

Neurotransmitter Receptors

NSE

Neuron-Specific Enolase

NSCLC

Non-Small Cell Lung Cancer

ORR

Objective Response Rate

OS

Overall Survival

PAK3

p21-Activated Kinase 3

PBMCs

Peripheral Blood Mononuclear Cells

PD-1

Programmed Cell Death Protein 1

PD-L1

Programmed Death-Ligand 1

PDXs

Patient-Derived Xenografts

PFS

Progression-Free Survival

PKA

Protein Kinase A

PMNs

Polymorphonuclear Neutrophils

PP2A

Protein Phosphatase 2

RAS

Renin-Angiotensin System

RFS

Recurrence-Free Survival

REST

RE1-Silencing Transcription Factor

SCLC

Small Cell Lung Cancer

SD

Standard Deviation

SERT

Serotonin Transporter

SH2B3

SH2B Adaptor Protein 3

SLC1A1

Solute Carrier Family 1 Member 1

SNS

Sympathetic Nervous System

SOX2

SRY-Box Transcription Factor 2

SRRM

Subregion Radiomics Model

SSRI

Selective Serotonin Reuptake Inhibitor

STAT3

Signal Transducer and Activator of Transcription 3

TAMs

Tumor-Associated Macrophages

TAZ

Transcriptional Co-activator with PDZ-binding Motif

TGFβ1

Transforming Growth Factor Beta 1

TKI

Tyrosine Kinase Inhibitor

TMB

Tumor Mutational Burden

TME

Tumor Microenvironment

TNF-α

Tumor Necrosis Factor-Alpha

TPH1

Tryptophan Hydroxylase 1

TRAIL

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

TSP-1

Thrombospondin-1

VEGF

Vascular Endothelial Growth Factor

YTHDC1

YTH Domain Containing 1

α5-nAChR

Alpha 5 Nicotinic Acetylcholine Receptor

β2-AR

Beta-2 Adrenergic Receptor

Author contributions

JZ, YH, and YL were responsible for conceptualization, Methodology, and Writing – original draft. YL, YS, YB, and JC were responsible for investigation, Methodology, and Visualization. CH, YY, and CZ prepared the figures and tables. CL made a significant contribution to the manuscript revision. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82373044), Natural Science Foundation of Shandong Province (No. ZR2023LSW023) and Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501900 & 2023ZD0501904 & 2023ZD0501905).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

No ethics approval was required for this review that did not involve patients or patient data.

Consent for publication

All authors consent to publication.