Neuro-tumor interactions: Multi-dimensional mechanisms of neurotransmitter regulation in tumor immune evasion and metabolic reprogramming

Abstract

Neurotransmitter-mediated regulation plays a multi-dimensional role in the tumor microenvironment, profoundly influencing key processes such as tumor immune evasion, metabolic reprogramming, and metastasis. However, the upstream regulatory mechanisms linking neural inputs to immune evasion and metabolic reprogramming remain incompletely understood. We systematically summarize current evidence from molecular, cellular, and immunological studies to elucidate how neurotransmitter-dependent mechanisms drive dynamic changes in the tumor microenvironment through the regulation of tumor cells and immune cells, and map the complex interaction networks between the nervous system and tumor progression. We propose a unifying “neuro-metabolic-immune axis” framework that highlights the dual role of neurotransmitters in suppressing anti-tumor immunity and facilitating tumor adaptation. By mapping this axis, we reveal new insights into tumor ecology and identify neural pathways as promising therapeutic targets. Targeting these pathways may enhance immunotherapy and disrupt tumor-supportive metabolism, offering new directions in precision oncology.

Key Words: Tumor microenvironment; Neurotransmitter signaling; Metabolic reprogramming; Immune evasion; Immunotherapy

Core Tip: This article presents a novel perspective on the role of neural signaling in orchestrating tumor progression through the neuro-metabolic-immune axis within the tumor microenvironment. It illustrates that neurotransmitters can directly regulate immune evasion while also mediating metabolic reprogramming, thereby indirectly facilitating immunosuppression. This integrative framework unveils a dynamic bidirectional network wherein neural signals coordinate both metabolic and immune adaptations, offering new therapeutic targets aimed at disrupting this axis to enhance conventional cancer treatments.

INTRODUCTION

Cancer remains one of the leading causes of death worldwide. In 2020, there were an estimated 19.3 million new cancer cases and 10 million cancer-related deaths globally. This burden is projected to rise further, reaching approximately 20 million new cases and 10 million deaths by 2025, underscoring cancer’s persistent and escalating impact on global public health[1]. The biological heterogeneity and complexity of cancer significantly challenge conventional therapeutic approaches[2]. In recent years, advances in immunotherapy and metabolism-targeted treatments have emphasized the tumor microenvironment (TME) as a central regulatory nexus influencing cancer progression and response to therapy[3]. While the mechanisms of immune evasion and metabolic reprogramming have been widely studied, the upstream regulatory systems that orchestrate these processes remain incompletely understood. The nervous system is increasingly recognized as a cross-system integrator in cancer biology, capable of shaping the TME through modulation of immune activity, metabolic states, and neurochemical signaling[4].

In recent years, the crucial role of the nervous system in tumor progression has gradually been revealed. For instance, the impact of psychological stress on tumor progression has been confirmed in several studies, with the nervous system playing an important role in this process, particularly in regulating immune responses and the TME. Research has shown that excessive activation of the sympathetic nervous system (SNS) may lead to the disruption of body homeostasis, promoting tumor formation and progression[5]. The nervous system mediates extensive interactions with tumor cells and their microenvironment through neurotransmitters, neuropeptides, and extracellular vesicles like exosomes, regulating tumor initiation, proliferation, invasion, and metastasis[6-8]. The nervous system can not only directly drive tumor cell proliferation, but also additionally modulate immune cell functions to facilitate tumor immune evasion[9,10]. Furthermore, in certain cancers, such as prostate cancer, mechanisms like tumor axonogenesis and neurogenesis further highlight the complexity of neural components in the TME[11]. The density and distribution of nerve fibers may even serve as prognostic biomarkers, providing a basis for personalized treatment[12]. These studies reveal the multidimensional regulatory role of the nervous system in the TME, involving immune modulation, metabolic reprogramming, and tumor cell proliferation and invasion. A deeper understanding of the molecular mechanisms underlying neuro-tumor communication not only provides a new perspective for elucidating tumor biological behavior but also lays a theoretical foundation for developing novel cancer treatment strategies targeting neuro-regulation. This paper aims to summarize the progress in understanding the neuro-regulation of tumorigenesis, with a particular focus on the key roles of neurotransmitter signaling in tumor immune evasion and metabolic reprogramming, and explore the potential therapeutic implications of targeting neural signaling in cancer treatment, providing new perspectives and a theoretical foundation for future research.

CORE REGULATORY MECHANISM OF NEURO-IMMUNE AXIS

Sympathetic/parasympathetic nerve signals

The SNS plays a crucial role in tumor progression through the release of norepinephrine (NE), which influences immune cell polarization and function. NE activates β-adrenergic receptor (β-AR) on tumor-associated macrophages (TAMs), promoting their polarization toward the M2 phenotype. This M2 polarization supports tumor growth by enhancing immune suppression and promoting tissue remodeling, which creates a more favorable environment for tumor expansion. Additionally, SNS signaling via NE contributes to the exhaustion of CD8+ T-cells by upregulating inhibitory receptors such as programmed death 1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein 3, which impairs the cytotoxic function of these immune cells. Chronic stress, which elevates NE levels, accelerates tumor progression by further enhancing vascularization within the tumor and promoting immune escape. These processes allow tumors to evade immune surveillance and metastasize more effectively[13-15].

In contrast, parasympathetic nervous system signaling, primarily through acetylcholine (ACh), generally exerts anti-inflammatory effects that help regulate immune responses in the TME. ACh activates the cholinergic anti-inflammatory pathway, binding to α7-nicotinic ACh receptors on immune cells such as macrophages, inhibiting the release of pro-inflammatory cytokines like interleukin-6 and tumor necrosis factor-α (TNF-α). This dampening of inflammation helps regulate excessive immune responses in the TME, potentially preventing inflammation-related tumor progression and supporting immune responses against the tumor. However, in some contexts, ACh can also facilitate immune evasion by promoting the expansion of regulatory T cells (Tregs), which suppresses anti-tumor immune responses, and by inhibiting the infiltration of cytotoxic T cells into tumors. This paradoxical effect highlights ACh’s dual role in cancer: While it can modulate inflammation, it can also contribute to immune escape, thereby supporting tumor survival and progression[16,17].

Neuropeptides

Neuropeptides are an important means through which the nervous system directly regulates tumor immunity. Among them, calcitonin gene-related peptide (CGRP) and substance P, primarily released from sensory neurons, have been shown to modulate immune responses in the TME. CGRP can suppress CD8+ T-cell infiltration and function in tumors, thereby facilitating immune escape and tumor progression. This effect is reversible, as blocking CGRP signaling can enhance T cell responses and improve therapeutic outcomes such as those of radiotherapy and checkpoint inhibition[18,19]. CGRP is also involved in shaping the innate immune landscape, including inhibition of group 2 innate lymphoid cells and promoting M2-like macrophage polarization via the phosphoinositide 3-kinases/protein kinase B pathway, which contributes to immunosuppressive conditions in tumors[20,21]. Substance P, through its receptor neurokinin-1 receptor, has pro-inflammatory effects in general immune contexts, but in tumors, it has been associated with enhanced immunosuppressive activity driven by both TAMs and myeloid-derived suppressor cells (MDSCs)[22]. Neuropeptide Y has also been implicated in immune modulation, with studies indicating that it may influence T cell activity and Tregs function in a receptor- and dose-dependent manner[23]. In addition, neuropeptides influence immune activity by interacting with inflammasome and cytokine signaling. CGRP, for example, can inhibit NLRP3 inflammasome activation in macrophages, reducing interleukin-1β release and limiting inflammatory responses under infection-related conditions[24].

5-hydroxytryptamine in immune regulation

5-hydroxytryptamine (5-HT), beyond its classical role as a neurotransmitter, is increasingly recognized as an immunomodulatory molecule that actively shapes both innate and adaptive immune responses. A variety of immune cells—including T cells, macrophages, dendritic cells, and monocytes—express 5-HT receptors (e.g., 5-HT1, 5-HT2, 5-HT3, and 5-HT7) and can also synthesize or uptake 5-HT from the environment. Through these receptors, 5-HT regulates immune cell proliferation, cytokine production, and differentiation. For instance, 5-HT promotes T cell activation and modulates the T helper 17 cell/Treg balance, while also driving dendritic cell maturation and functional polarization. In macrophages, 5-HT signaling influences the shift between pro-inflammatory M1 and anti-inflammatory M2 phenotypes, suggesting that 5-HT contributes broadly to immune homeostasis and the resolution of inflammation[25,26].

Recent studies further reveal that different 5-HT receptors mediate distinct immunological outcomes. The 5-HT7 receptor, for example, can enhance the secretion of interleukin-6 and TNF-α in monocytes and microglia, while activation of the 5-HT3 receptor has been associated with modulation of cytokine release via p38 mitogen-activated protein kinase signaling. These receptor-specific pathways highlight 5-HT’s nuanced role in immune signaling. In the context of tumor immunology, 5-HT can contribute to immune evasion by promoting immunosuppressive cell phenotypes—such as M2 macrophages and Tregs—within the TME. At the same time, antagonizing certain 5-HT receptors has been shown to restore anti-tumor immune activity, indicating that serotonergic pathways may be viable targets in cancer immunotherapy[27-29].

CORE CHARACTERISTICS OF TUMOR METABOLIC REGULATORY NETWORK

Driving factors of metabolic reprogramming

Warburg effect: The Warburg effect, a hallmark of cancer metabolism, refers to the preference of cancer cells for glycolysis over oxidative phosphorylation even in the presence of sufficient oxygen. This phenomenon, first observed by Otto Warburg in the early 1920s, has since been identified as a key feature of tumor cell metabolism. The driving factors behind the Warburg effect are multifaceted and involve both genetic mutations and alterations in signaling pathways. Key contributors include hypoxia-inducible factors, cellular myelocytomatosis oncogene, and mutations in tumor suppressors, such as p53, which collectively promote the reprogramming of cancer cell metabolism[30]. These factors regulate the expression of crucial enzymes involved in glycolysis, such as hexokinase, phosphofructokinase, and pyruvate kinase isoform M2, which facilitate the rapid consumption of glucose and the production of lactate, even under normoxic conditions[31]. Additionally, the altered TME, characterized by low oxygen levels, acidic conditions, and nutrient deprivation, further enhances the reliance on glycolysis as the primary energy source, ensuring continuous cell proliferation and survival[32]. This metabolic shift not only supports cancer cell growth but also promotes immune evasion and resistance to conventional therapies, making the Warburg effect a central driver of tumor progression[30].

Glutamine metabolism dependency: Tumor cells often exhibit a heightened dependency on glutamine metabolism, a key feature of their metabolic reprogramming. This dependency is driven by the need for glutamine to support rapid cell proliferation and maintain tumor survival. Glutamine, though a non-essential amino acid, is consumed at significantly higher rates by cancer cells due to the upregulation of specific transporters, such as solute carrier family 1, member 5, and enzymes like glutaminase, which facilitate enhanced glutamine uptake and its catabolism[33]. This reprogrammed metabolism supports the replenishment of tricarboxylic acid cycle intermediates through anaplerosis, which in turn fuels critical biosynthetic pathways for nucleotides, amino acids, and lipids—key building blocks for rapidly dividing cancer cells[34]. Furthermore, glutamine-derived α-ketoglutarate plays a crucial role in epigenetic regulation, influencing tumorigenesis by modulating gene expression and chromatin structure. In hypoxic environments, glutamine also supports oxidative phosphorylation, providing energy even in the absence of adequate glucose[35]. These adaptations, however, are not uniform across all cancer types, with specific TME and genetic mutations influencing the extent of glutamine dependency. This metabolic heterogeneity highlights the potential for targeting glutamine metabolism as a therapeutic strategy for cancer treatment[36].

Enhanced lipid metabolism: Lipid metabolic reprogramming has emerged as a crucial driver of cancer progression, enabling tumor cells to adapt to the hostile TME characterized by low oxygen and nutrient availability. The reprogramming of lipid metabolism pathways supports tumor growth by providing essential building blocks for cell membranes, signaling molecules, and energy storage. One of the key mechanisms is the increased lipid uptake, particularly through transporters like CD36, fatty acid transfer proteins, and fatty acid binding proteins, which are upregulated in various cancers, including breast and ovarian cancers[37,38]. Moreover, tumor cells upregulate de novo lipogenesis to sustain their rapid growth, utilizing acetyl-CoA for fatty acid synthesis, which is facilitated by enzymes such as fatty acid synthase[39]. These metabolic alterations also extend to the TME, where stromal and immune cells undergo lipid reprogramming, further promoting an immunosuppressive environment that favors tumor progression[40]. The enhanced lipid metabolism not only supports the structural and energy needs of tumor cells but also modulates intracellular signaling pathways that contribute to malignant phenotypes, including metastasis and resistance to therapy[41].

Regulation of the tumor immune microenvironment by metabolites

Lactate contributes to the immunosuppressive microenvironment: Lactate, a metabolic byproduct of glycolysis, plays a significant role in shaping the immune-suppressive microenvironment in cancer and chronic inflammatory diseases. In the TME, the rapid glycolysis of tumor cells leads to high lactate levels, which contribute to local hypoxia and acidification. These conditions impair the function of effector immune cells, such as cytotoxic T cells and natural killer cells, by reducing glucose uptake and forcing these cells into metabolic stress, thus inhibiting their proliferation and cytokine production. Additionally, lactate fosters the polarization of immunosuppressive cells, such as Tregs and MDSCs, both of which contribute to immune evasion and promote tumor growth[42,43]. Lactate also directly influences macrophage polarization, shifting them toward an M2-like phenotype, which further reinforces the immunosuppressive environment and aids in tumor progression[44]. This dual role of lactate in fueling both metabolic and immune suppression highlights its pivotal function in cancer immunology.

Beyond its metabolic impact, lactate also induces epigenetic changes that contribute to the suppression of immune responses. Lactate promotes histone acetylation in macrophages, which leads to the transcriptional repression of pro-inflammatory cytokines and genes crucial for immune activation. This epigenetic modification not only weakens the inflammatory response but also leads to a form of “trained immunosuppression”, where immune cells, particularly macrophages, exhibit a diminished capacity to respond to subsequent inflammatory signals. This effect of lactate extends beyond cancer to other inflammatory conditions, such as rheumatoid arthritis and multiple sclerosis, where it similarly contributes to immune dysregulation[39,45]. The accumulation of lactate in these various pathological conditions underscores its role as a key modulator of immune responses, influencing both chronic inflammation and cancer progression[42,43].

Glutamine metabolic competition shapes the immunosuppressive microenvironment: Glutamine metabolism plays a pivotal role in shaping the immunosuppressive TME by influencing the function and phenotype of both innate and adaptive immune cells. In the TME, glutamine depletion caused by tumor cells not only impairs T cell effector function but also drives the reprogramming of tumor-associated immune cells toward suppressive phenotypes. For example, G protein-coupled receptor 109A+ myeloid cells, induced under glutamine-starved conditions via endoplasmic reticulum stress and the inositol-requiring enzyme 1α/X-box binding protein 1 axis, promote the accumulation of M2 phenotype TAMs and MDSCs, which inhibit CD8+ T cell responses[46,47]. Concurrently, TAMs can undergo metabolic reprogramming under glutamine-deficient and hypoxic conditions, shifting toward increased glutaminolysis, which supports their M2 phenotype through production of metabolites such as α-ketoglutarate. This metabolite not only fuels oxidative phosphorylation and fatty acid oxidation but also modulates epigenetic programs via Jmjd3-dependent mechanisms to sustain M2 activation[48,49]. Moreover, in renal cancer, local glutamine deprivation triggers interleukin-23 secretion from TAMs via hypoxia-inducible factor 1α activation, which in turn promotes Tregs expansion and suppresses cytotoxic lymphocyte activity, further contributing to immune evasion[50]. In dendritic cells, particularly type 1 conventional dendritic cells, glutamine uptake through the solute carrier family 38, member 2 transporter is essential for maintaining their cross-priming capacity and promoting CD8+ T cell responses. However, competition with tumor cells for glutamine can suppress these critical functions[47]. Notably, systemic glutamine blockade through prodrug-based inhibitors can impair tumor metabolic activity while simultaneously reprogramming the TME to enhance T cell infiltration and improve responsiveness to immunotherapy, highlighting the therapeutic potential of exploiting the differential glutamine metabolic flexibility between tumor and immune cells[51]. In summary, glutamine metabolism serves as a central axis in the metabolic crosstalk between tumor and immune cells, orchestrating an immunosuppressive niche that facilitates tumor progression and immune evasion, and thereby represents a critical target for therapeutic intervention in cancer immunometabolism.

Lipid metabolism as a driver of immunosuppressive TME: Lipid metabolism plays a critical role in shaping the immunosuppressive TME by influencing immune cell function and promoting immune evasion by tumor cells. In response to the nutrient and oxygen scarcity in the TME, tumor cells upregulate lipid uptake, synthesis, and oxidation to sustain their growth. This metabolic reprogramming leads to an accumulation of lipids, particularly fatty acids, within immune cells such as CD8+ T cells and Tregs, impairing their anti-tumor functions. For instance, excess lipids in CD8+ T cells, due to increased lipid uptake via CD36 and other transporters, hinder their secretion of critical cytokines like interferon-gamma and TNF-α, diminishing their cytotoxic activity against tumor cells[38,52]. Moreover, TAMs and MDSCs also undergo lipid metabolic reprogramming, enhancing their immunosuppressive functions and promoting tumor progression[38]. Additionally, the activation of sterol regulatory element-binding proteins in Tregs drives fatty acid synthesis, contributing to their functional specialization and further suppressing anti-tumor immune responses[53]. This lipid-driven metabolic reprogramming not only affects immune cell function but also reshapes the interactions between tumor cells and stromal cells, further reinforcing a pro-tumor immune environment. Collectively, these findings also suggest that targeting lipid metabolism in the TME could offer a promising therapeutic strategy to enhance anti-tumor immunity[54].

INTERACTION BETWEEN NEURO-IMMUNE AXIS AND METABOLIC NETWORK

Neural signals drive metabolic reprogramming

Sympathetic adrenergic signaling mediates metabolic reprogramming: Sympathetic adrenergic signaling plays a critical role in regulating metabolic reprogramming, a key feature of cancer cell metabolism. The release of NE from the SNS binds to β-AR on immune cells and tumor cells, modulating their metabolic activities. In immune cells, NE–β-AR signaling suppresses glycolysis by downregulating the expression of glucose transporter 1, which is essential for glucose uptake and effective immune function[55]. In addition to immune cells, chronic stress and adrenergic signaling also modulate tumor metabolism by enhancing glycolysis. For example, chronic stress-induced release of epinephrine activates the β2-adrenergic receptor (β2-AR)/protein kinase A/cAMP responsive element binding protein 1 pathway, increasing the expression of glycolytic enzymes such as hexokinase 2 and phosphofructokinase, thus promoting colorectal cancer (CRC) progression[56]. This metabolic shift towards glycolysis under adrenergic stress enables tumor cells to meet their high energy demands, crucial for sustaining rapid cell growth and proliferation. By enhancing glucose availability and facilitating the production of metabolic intermediates, this shift supports tumor cells in adapting to their high-energy needs, promoting both tumor growth and metastasis[57]. Additionally, chronic stress-induced epinephrine stabilizes the ubiquitin-specific peptidase 22 protein, which promotes the expression of forkhead box protein O1, leading to the activation of adipose triglyceride lipase-mediated lipolysis and driving breast cancer metastasis. Inhibiting ubiquitin-specific peptidase 22 can block this signaling pathway, thus suppressing epinephrine-induced breast cancer metastasis[58]. In conclusion, metabolic reprogramming can bring about complex changes to the TME and profoundly influence tumor progression, while sympathetic adrenergic signaling acts as one of the ways in neural regulation to mediate metabolic reprogramming.

Regulation of metabolic reprogramming by 5-HT: Beyond its traditional role as a neurotransmitter, 5-HT not only directly regulates the immune microenvironment as mentioned earlier to influence immune function, but also has a role worth exploring in regulating metabolism. In peripheral tissues, 5-HT regulates metabolic processes by influencing insulin secretion in pancreatic β-cells and modulating lipogenesis and lipolysis in adipocytes, highlighting its role in metabolic regulation[59]. In cancer, 5-HT metabolism is altered, contributing to tumor progression by enhancing cell proliferation, invasion, and angiogenesis through complex mechanisms, including receptor-mediated signaling and the serotonylation of proteins such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH)[60]. In immune cells, particularly CD8+ T cells, 5-HT influences glycolytic metabolism by promoting the serotonylation of GAPDH, which shifts the metabolic phenotype toward glycolysis, supporting enhanced immune activity in the TME[61]. Moreover, 5-HT is also involved in regulating gluconeogenesis in the liver through its action on specific 5-HT receptors, further illustrating its capacity to control systemic metabolic processes[62]. Collectively, these findings underscore the multifaceted role of 5-HT in metabolic reprogramming, where it not only maintains systemic energy homeostasis but also adjusts metabolic pathways to support tumor progression and immune responses.

Neural signal-mediated metabolic reprogramming induces immune escape

The β2-AR, activated by catecholamines such as NE, plays a critical role in suppressing CD8+ T-cell function. This suppression occurs through the inhibition of the metabolic reprogramming that is essential for T-cell activation and effector function. Under normal conditions, T-cell activation triggers an increase in glucose uptake and glycolysis, which are essential for providing the energy required for immune responses. However, activation of the β2-AR by NE reduces the expression of glucose transporter 1 on T-cells, impairing glucose uptake and glycolysis[55]. Moreover, β2-AR signaling also negatively impacts mitochondrial function, further dampening the metabolic capacity of CD8+ T-cells and weakening their ability to generate the energy necessary for an effective immune response. This metabolic blockade leads to a failure in T-cell activation, thereby promoting immune evasion within the TME[63]. In contrast, 5-HT has a dual role in the TME, which complicates its impact on immune responses. On one hand, 5-HT can enhance the activation and function of CD8+ T-cells by promoting glycolytic metabolism through a post-translational modification of GAPDH via serotonylation. This modification enhances GAPDH activity, which is crucial for the glycolytic shift required during T-cell activation and antitumor immune responses[61]. On the other hand, 5-HT also promotes immunosuppressive conditions within the TME, particularly when it accumulates in excess or is dysregulated. For instance, 5-HT interacts with the phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin pathway in tumor cells, driving metabolic reprogramming that supports tumor growth and metastasis. This metabolic shift increases the production of immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-β, which not only dampen T-cell activity but also promote the recruitment of MDSCs and Tregs to the TME, further hindering effective immune responses[64].

Based on the above discussion, we have uncovered the intricate and dynamic interplay between the neuro-immune axis and the metabolic network, highlighting the critical role of neural signals in orchestrating metabolic reprogramming within the TME. These findings point to a central insight: Neural regulation of metabolism not only fulfills the energetic demands of tumor cells but also reshapes the immune landscape, thereby profoundly influencing tumor immune evasion and progression. Notably, this regulatory mechanism exhibits a dual nature—capable of enhancing antitumor immune responses or, conversely, facilitating immunosuppression and tumor advancement. Thus, a deeper understanding of how neural signals precisely modulate metabolic pathways and immune function is essential. Such insight holds promise for elucidating the systemic underpinnings of tumor biology and for guiding the development of innovative therapeutic strategies targeting the neuro-metabolic-immune axis.

POTENTIAL OF TARGETING NEURAL SIGNALS IN CANCER THERAPY

In recent years, although significant progress has been made in cancer treatment, especially in immunotherapy and targeted therapies, many patients still face the issue of poor treatment outcomes. Tumor immune evasion, therapy resistance, and the complexity of the TME remain major challenges in current treatment strategies. While conventional therapies such as chemotherapy and immune checkpoint inhibitors (ICIs) can sometimes effectively prolong patient survival, their effectiveness is still limited due to tumor cell adaptability and immune suppression. As a result, exploring new therapeutic targets and strategies, particularly targeting neural signaling pathways within the TME, has become an important task in cancer research.

Potential of β-blockers in cancer therapy

Traditionally used for treating cardiovascular diseases, β-blockers (BBs) have been shown to inhibit epinephrine/NE-mediated immune evasion in several tumor models[14,15,58,65]. To identify relevant studies, we performed a focused literature search using the PubMed database. The search strategy used the following Boolean logic: (“propranolol” OR “beta-blocker”) AND (“cancer” OR “tumor”) AND “clinical trial”. Articles published before March 2025 in English were considered. While clinical trials were prioritized, one translational and preclinical study involving murine models was also included due to its mechanistic significance and clinical relevance. These studies are summarized in Table 1[66-72].

Table 1 Propranolol-based cancer trials.

Cancer	Study design	Drug	Main results	Sample size	Year
BC	Phase II RCT	Propranolol + etodolac	Reduced Ki-67, inflammatory cytokines, and pro-metastatic gene expression[62]	38	2018
MM	Phase I clinical trial	Propranolol + pembrolizumab	Safe with 78% objective response rate and biomarker modulation[63]	9	2021
BC	Phase II feasibility study	Propranolol + neoadjuvant chemotherapy	Feasible with 96% adherence, no major safety issues[64]	10	2021
CRC	Translational and preclinical study	Propranolol	Activated CD8+ T cells, suppressed AKT/MAPK signaling[65]	Unknow	2020
OC	Prospective pilot clinical trial	Propranolol + chemotherapy	Feasible with cytokine modulation and improved QOL[66]	26	2019
CRC	RCT	Propranolol + etodolac	Improved EMT and immune markers, and reduced recurrence trend[67]	34	2020
BC	Phase II RCT	Propranolol + etodolac	Reduced EMT and inflammation, and improved NK cell markers[68]	38	2017

BC: Breast cancer; MM: Melanoma; CRC: Colorectal cancer; OC: Ovarian cancer; RCT: Randomized controlled trial; QOL: Quality of life; EMT: Epithelial-mesenchymal transition; NK cell: Natural killer cell; AKT: Protein kinase B; MAPK: Mitogen-activated protein kinase.

Synergistic effect of BBs with immunotherapy: ICIs have become a breakthrough in cancer treatment, yet many patients still do not benefit from them. Studies have found that SNS activation can suppress CD8+ T cell activity through β2-AR and promote the recruitment of immunosuppressive cells (such as MDSCs and Tregs), weakening the effects of immunotherapy[73]. It has been shown that BBs can counteract these effects by enhancing CD8+ T cell function and reducing immune suppression in the TME, thereby improving the effectiveness of ICIs[69]. Clinical studies have shown that BBs can improve the disease control rate and extend the duration of treatment in patients receiving ICI therapy. For example, in melanoma patients, propranolol combined with PD-1 inhibitors increased the objective response rate to 78%, which was significantly higher than the 46% observed with PD-1 inhibitors alone[67]. Additionally, BBs enhance T cell infiltration, reduce MDSCs, and improve the TME, further supporting their potential as immunotherapy enhancers[74].

BBs enhance chemotherapy efficacy: Chemotherapy remains the cornerstone of cancer treatment, but tumor resistance limits its efficacy. Studies have shown that BBs can enhance chemotherapy sensitivity by reducing SNS activity[73]. In a triple-negative breast cancer mouse model, propranolol combined with anthracycline chemotherapy (e.g., doxorubicin) significantly reduced distant metastasis and lowered NE levels in the TME, inhibiting β2-AR-mediated pro-cancer signaling[75]. Furthermore, in a CRC model, propranolol reduced the expression of carbonic anhydrase IX in the TME, disrupting hypoxic adaptation and enhancing the effect of fluorouracil chemotherapy[76].

Intervention of 5-HT signaling

In recent years, several studies have revealed the negative regulatory role of 5-HT in tumors, making it a potential anti-tumor therapeutic target. In various mouse tumor models, peripheral depletion of 5-HT significantly inhibited tumor growth, prolonged survival, enhanced CD8+ T cell infiltration and effector function, and downregulated the expression of the immune-suppressive molecule PD-L1 on tumor cells. Drug interventions such as selective 5-HT reuptake inhibitors (e.g., fluoxetine) and tryptophan hydroxylase 1 inhibitors (e.g., telotristat) showed anti-tumor effects similar to genetic depletion and synergized with PD-1 antibodies to significantly improve immunotherapy response rates[77].

Moreover, research targeting the 5-HT receptor 5-hydroxytryptamine receptor 2B further deepens the potential of 5-HT-targeted strategies. In CRC, high expression of HTR2B is associated with poor prognosis, and antagonists such as SB204741 and GM-60186 can significantly inhibit cancer cell proliferation and migration by suppressing the extracellular regulated protein kinases signaling pathway, reducing cyclin D1 expression, and inducing apoptosis[78]. Another study indicated that HTR2B promotes CRC metastasis through the cAMP responsive element binding protein 1-zinc finger E-box binding homeobox 1 axis driving epithelial-mesenchymal transition, and the use of specific antagonists like RS127445 effectively suppressed metastatic foci formation[79].

Targeting nerve growth factor-TrkA axis

Nerve growth factor (NGF) and its receptor TrkA play crucial roles in tumor immune evasion, therapy resistance, and tumor-neural interactions. Research suggests that NGF plays a significant role in tumor progression by promoting neurogenesis and neural reprogramming. This makes NGF a potential therapeutic target, especially in the context of nerve-cancer interactions[80].

In melanoma, NGF suppresses tumor cells’ response to immune factors such as interferon-gamma, reducing CD8+ T cell and natural killer cell infiltration in the TME, thus promoting immune evasion. Inhibiting NGF or its receptor TrkA significantly enhances the efficacy of immunotherapy, boosting T cell function and memory cell generation[81]. Furthermore, the chemotherapy drug doxorubicin upregulates NGF expression, promoting sympathetic nerve growth in tumors and exacerbating tumor growth and chemotherapy-induced neuropathic pain. Targeting NGF signaling not only enhances immune responses but also alleviates chemotherapy side effects[82].

In pancreatic cancer studies, high expression of the Trk receptor is associated with poor prognosis. Targeting the NGF signaling pathway can inhibit tumor neurogenesis, improve the immune microenvironment, and enhance chemotherapy efficacy[83]. Additionally, high expression of the NGF receptor (NGFR) in melanoma is closely linked to immune resistance. Cells with high NGFR expression reduce T cell infiltration and immune rejection, significantly weakening the treatment response. Inhibiting NGFR or its downstream pathways can restore immunotherapy sensitivity and enhance therapeutic effects[84].

Targeting neural signaling pathways in cancer therapy opens up new avenues for treatment. Its innovation lies in focusing not only on tumor cells themselves but also on regulating the TME and immune evasion mechanisms. This approach can enhance the effects of immunotherapy and increase chemotherapy sensitivity. However, this strategy also faces challenges, particularly the potential side effects from tumor heterogeneity and the widespread effects of the nervous system, which may limit its clinical applicability. Despite these challenges, the strategy of targeting neural signals holds great research potential, and as research progresses, it may become a critical complement to cancer treatment, driving an overall transformation in therapeutic approaches.

RESEARCH CHALLENGES AND FUTURE DIRECTIONS

The complex interplay between the nervous system and cancer biology, as illustrated in this study, reveals a paradigm shift in our understanding of tumor progression. Traditionally viewed as a disease of uncontrolled cellular proliferation, cancer is now increasingly recognized as a systemic disorder influenced by neuroimmune and metabolic dynamics. However, while the evidence supports a robust role for neurotransmitter signaling in shaping tumor behavior and immune evasion, critical gaps and contradictions remain, warranting a deeper, more nuanced exploration.

One of the most compelling—but underexplored—aspects of neuro-tumor interaction lies in its bidirectionality. While the nervous system clearly influences tumor progression, tumors themselves may remodel neural circuits through axonogenesis and neurogenesis[85]. This reciprocal feedback loop suggests that tumors can “educate” the nervous system to establish a more permissive niche. Yet, current therapeutic strategies predominantly target the outbound influence of neural signals on the tumor, neglecting the inbound modulatory potential of tumors on neural function. This raises provocative questions: Could tumors induce neuroplastic changes akin to those seen in chronic pain or depression? Could such changes be harnessed or reversed therapeutically?

Moreover, the duality of neurotransmitter functions introduces a significant therapeutic dilemma. For instance, both ACh and serotonin exhibit paradoxical roles—alternately promoting immune regulation and immune evasion depending on context, dosage, and receptor subtype expression[16,17,27-29]. These functional bifurcations challenge the binary classification of neurotransmitters as “pro-“ or “anti-“ tumorigenic and underscore the necessity of precision neuropharmacology. Rather than blunt inhibition or activation, future therapies may need to rely on spatiotemporal modulation of specific receptor subtypes within defined microenvironments.

Another dimension ripe for exploration is the intersection of neural signaling with metabolic fitness of immune cells. While the Warburg effect and glutamine addiction are well-characterized for tumor cells[30,36], emerging evidence suggests that neuro-mediated metabolic suppression of cytotoxic T cells is a major bottleneck in immunotherapy[55,63]. The β2-adrenergic suppression of glycolytic flux in CD8+ T cells illustrates how metabolic checkpoints are not merely intrinsic but can be exogenously imposed by stress-derived neurotransmitters[55]. This reframes adrenergic signaling not just as a passive contributor to immune suppression, but as an active metabolic switch—raising the possibility that targeting neuro-metabolic axes might revive “metabolically paralyzed” immune cells within the TME.

Importantly, this paper also raises a philosophical and practical debate regarding the therapeutic implications of targeting such deeply conserved and widely expressed systems as neurotransmitter pathways. The systemic effects of BBs or serotonin modulators, for example, might extend beyond tumors to influence cognition, mood, cardiovascular tone, and gut physiology[86-89]. This highlights a crucial ethical and clinical balancing act: Can we disrupt tumor-supportive neurobiology without disrupting systemic neurophysiology? The answer may lie in localized delivery methods, nanomedicine, or engineering of receptor-selective ligands that exhibit TME-specific activation.

Finally, the emerging convergence of cancer neuroscience with systems immunology and metabolism invites the construction of integrative models. Such models must go beyond correlative omics to map causal signaling hierarchies and feedback loops across the neuro-immune-metabolic triad. This interdisciplinary approach may unlock a new generation of therapeutic strategies—ones that do not merely kill tumor cells but restore systemic immune competence, recalibrate metabolic resilience, and rewire neurophysiological balance.

CONCLUSION

This paper underscores that neural regulation contributes to tumor immune evasion not only by directly modulating immune cells, but also by reprogramming tumor metabolism in ways that suppress immune responses. By proposing the concept of a neuro-metabolic-immune axis, this study offers a unified framework that integrates neural-immune interactions with metabolic modulation, thereby providing a more comprehensive understanding of how the nervous system shapes the TME. Based on current evidence, we also outline the mechanistic rationale for targeting neural signaling pathways as a feasible and promising therapeutic strategy. While emerging studies suggest the potential of targeting neural signaling pathways in cancer, several limitations remain: Clinical validation is still limited, the systemic physiological consequences of neural modulation are not fully understood, and this paper may not exhaustively capture the complexity and diversity of neuro-metabolic-immune interactions across all tumor types. Further in-depth and translational research is warranted to fully harness this axis for clinical benefit.