Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.

Introduction

According to Global cancer statistics, tumors are responsible for nearly 10 million deaths per year worldwide, constituting approximately one in six deaths on a global scale [ 1 , 2 ]. The high mortality rate is primarily due to the rapid progression of common malignancies, highlighting the urgent need for a more profound understanding of tumor progression mechanisms, especially those related to metabolic and microenvironmental regulation [ 3 , 4 ].

The development of tumors is intricately driven by cellular reprogramming processes and dynamic interactions within the TME [ 5 ]. Comprising a diverse network of malignant cells, immune cells, endothelial cells, cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) components, the TME not only offers structural support but also significantly influences tumor metabolism [ 6 – 11 ]. This interplay influences tumor growth, invasion, and resistance to therapy. Altered metabolism plays a crucial role in these processes, allowing tumor cells to meet the heightened energy and biosynthetic demands associated with rapid proliferation. A key aspect of this reprogramming is the transition to aerobic glycolysis, known as the “Warburg effect”, where tumor cells prioritize biosynthetic intermediate production over efficient ATP synthesis [ 5 ]. Beyond glycolysis, tumor cells utilize other additional metabolic pathways such as lipid metabolism, glutamine metabolism, and amino acid metabolism [ 12 – 14 ]. Collectively, these pathways sustain tumor growth and actively contribute to the establishment of a tumor-promoting microenvironment.

While the SNS is traditionally known for its involvement in the “fight or flight” response, it has now been identified as a key regulator of tumor metabolism and progression [ 15 , 16 ]. Recent research emphasizes the significant role of the SNS in orchestrating metabolic adaptations and shaping the TME [ 15 , 17 ]. By activating ARs on tumor, and stromal cells via the release of neurotransmitters such as NE, the SNS reprograms key metabolic pathways, including glycolysis and fatty acid oxidation (FAO), which in turn not only fuel tumor growth but also promote immunosuppressive phenotypes within the TME [ 18 – 20 ]. These findings highlight the therapeutic potential of targeting SNS signaling to simultaneously modulate tumor metabolism and reshape the immune microenvironment, offering a promising strategy to disrupt tumor-promoting networks. This review provides a comprehensive overview of how the SNS orchestrates tumor progression through metabolic remodeling of tumor, immune, and endothelial cells. It systematically examines the roles of both systemic and local SNS signaling in shaping the metabolic landscape of the TME, with emphasis on glucose, lipid, and mitochondrial metabolism. By elucidating the molecular mechanisms and emerging therapeutic strategies targeting SNS activity, this review aims to bridge current knowledge gaps and foster integrative approaches for disrupting tumor-supportive neuro-metabolic circuits. To support this review, we conducted a comprehensive literature search using PubMed and Web of Science without time restrictions. Broad search terms related to the sympathetic nervous system (SNS), cancer biology, metabolism, immune modulation, and targeted therapy were employed to ensure inclusivity (Table 1 ). While specific terms such as “sympathetic metabolic regulation” and “tumor neuroscience” were not explicitly included in the automated search string to avoid the risk of missing relevant studies, these important subfields were thoroughly covered through manual screening of full texts and reference lists during the evaluation process.

Materials and methods

A comprehensive literature search was conducted to explore the role of the SNS in tumor progression and metabolic regulation. Two electronic databases, PubMed and Web of Science, were systematically searched without time restrictions.

To ensure both breadth and specificity, a predefined set of search terms related to SNS, cancer biology, metabolism, immunity, and targeted therapy were used in combination with Boolean operators. The detailed search strategy is provided in Table 1 . The initial search yielded approximately 2,200 articles. Two authors (Chen Sun and Tian Lu) independently screened titles and abstracts, followed by full-text evaluation based on inclusion and exclusion criteria. Additionally, relevant references from included studies and key reviews were manually screened to supplement the search.

SNS: systemic arm and local arm

The SNS exerts a multifaceted role in regulating tumor biology through its systemic arm and local arm, employing catecholamines, including epinephrine (E) and NE, as neuroeffector molecules to modulate the TME [ 21 ]. The systemic effects of the SNS are primarily mediated through the release of E from the adrenal medulla into the circulation (Figure. 1 ), with NE contributing partially to these effects. Circulating E and NE reach the tumor via the vasculature, where they bind to ARs expressed on tumor cells and stromal elements within the TME [ 22 , 23 ]. Beyond direct tumor interactions, E and NE modulate immune cell functions in peripheral and lymphoid tissues (Figure. 1 ), which can impact tumor progression in a context-dependent manner [ 24 , 25 ]. For example, stress has been shown to elevate the number of myeloid-derived suppressor cells (MDSCs) in both the peripheral blood and spleen (Figure. 1 ), thereby promoting breast cancer progression [ 26 ]. In addition to their direct effects on tumor and immune cells, these systemic effects complement local SNS actions by mobilizing energy substrates [ 21 ]. For example, E released from the adrenal medulla activates hepatic ARs to promote glucose mobilization, which helps sustain tumor cell metabolism during periods of stress or rapid growth [ 27 – 29 ]. Concurrently, SNS activation modulates adipose tissue metabolism, promoting lipid release through E signaling (Figure. 1 ). For example, E derived from the adrenal medulla can act on adipocytes to promote lipolysis, thereby increasing the availability of circulating free fatty acids that may serve as substrates for lipid biosynthesis in tumor cells [ 21 , 30 ].

The local arm of the SNS directly innervates organs including the liver, spleen and lymph nodes, releasing NE via sympathetic fibers (Figure. 1 ) [ 31 – 33 ]. These fibers are often associated with the vasculature and can extend dendritic processes into tumor parenchyma [ 21 , 34 ]. Locally released NE activates ARs on nearby tumor cells and stromal elements, triggering three key pro-tumor processes: metabolic reprogramming, immunoinvasion, and structural remodeling of the TME [ 35 – 38 ]. For example, prostate cancer exhibits abundant sympathetic nerve fibers, which have been implicated in promoting neuroendocrine differentiation (NED), angiogenesis, and expansion of immunosuppressive immune cell populations [ 39 – 41 ]. These localized actions create a permissive microenvironment that accelerates tumor invasion and metastatic spread.

As illustrated in Figure. 1 , Systemic SNS activation promotes hepatic glucose release, adipose tissue lipolysis, and expansion of immunosuppressive cells such as MDSCs, thereby increasing energy substrate availability and shaping a tumor-permissive immune profile [ 21 , 42 – 44 ]. Locally, NE released from sympathetic nerve fibers acts on ARS expressed by tumor, stromal, and immune cells to induce angiogenesis, ECM remodeling, and immune evasion within the TME [ 15 , 21 ]. This dual-axis regulation creates a feed-forward loop that not only drives tumor growth and metastasis but also establishes a self-reinforcing, pro-tumor niche.

SNS in tumor progression

Tumor progression encompasses two major processes: tumor growth and tumor metastasis. While uncontrolled local proliferation drives primary tumor expansion, metastatic dissemination to distant organs accounts for most cancer-related deaths. Emerging evidence indicates that the SNS plays an important regulatory role in both processes, regulating malignant expansion and dissemination through diverse mechanisms [ 21 , 45 , 46 ].

Tumor growth

The growth of a tumor is contingent upon three main processes: cellular proliferation, angiogenesis, and immune suppression. The SNS plays a pivotal role in these processes by releasing neurotransmitters such as NE and E, which activate ARs and activate downstream pathways in tumor and stromal cells.

SNS promotes tumor cell proliferation through multiple molecular pathways including cAMP-PKA, which stimulate cell cycle progression and enhance metabolic activity [ 47 , 48 ]. NE and E have been observed to upregulate key cell cycle regulators, including Cyclin D1 and MYC, thereby accelerating mitotic division [ 49 , 50 ]. This represents a fundamental mechanism by which SNS activation directly drives cell cycle progression and increases metabolic demand, indirectly heightening the need for neovascularization. Notably, beyond these broadly shared regulatory pathways, SNS also promotes tumor growth through tissue-specific mechanisms. In liver cancer, NE released from sympathetic nerve terminals promotes the secretion of sFRP1. This secreted factor facilitates the binding of Wnt16B to its receptor FZD7, thereby enhancing β-catenin activation and nuclear translocation. Additionally, sFRP1 upregulates Wnt16B expression in cancer cells, establishing an autocrine Wnt16B/β-catenin positive feedback loop that sustains tumor-promoting transcriptional programs, facilitating EMT, stemness, and proliferation [ 51 ]. In prostate cancer, NE-mediated signaling has been observed to promote cell proliferation, with specific mechanisms including induction of neuroendocrine prostate carcinoma (NEPC) [ 40 , 52 , 53 ]. This occurs via NE-driven activation of β2-adrenergic receptors, which initiates neuroendocrine differentiation characterized by cellular remodeling and increased expression of markers such as CHGB and SYP.​ Similar findings have been reported, in breast cancer, stress-induced E elevation in the bloodstream has been shown to enhance cancer stem cell-like properties promoting tumor growth [ 54 , 55 ].

Angiogenesis, a hallmark of tumor growth, is found to be significantly influenced by SNS signaling. Through β-AR activation, NE induces VEGF expression and promotes endothelial cell proliferation and migration, a pro-angiogenic effect observed in cancers such as nasopharyngeal carcinoma, prostate cancer, and melanoma [ 38 , 56 – 58 ]. Activation of the SNS has also been associated with increased expression of pro-inflammatory cytokines such as IL-6. Literature reports suggest that in melanoma, stress-induced activation of the sympathetic-adrenal-medullary (SAM) axis leads to high IL-6 expression, which in conjunction with VEGF, further stimulates angiogenic processes [ 21 , 58 ]. Thaker et al. [ 57 ] found that chronic stress promoted tumor growth and angiogenesis in a mouse model of ovarian cancer, increasing vessel density and causing abnormal vasculature, suggesting that activation of the SNS impairs vascular normalization, thereby limiting immune cell infiltration into the TME.

The immune microenvironment is modulated by the SNS, which suppresses effector immune cells and enhances immunosuppressive components [ 15 , 59 ]. NE has been shown to exert a negative impact on T cells and natural killer cells (NK), thereby diminishing their anti-tumor activity [ 60 – 62 ]. More specifically, NE suppresses CD8 + T cell infiltration and function by suppressing CXCL9 secretion and enhancing adenosine production through WNT7A/β-catenin signaling in tumor cells, ultimately leading to resistance to anti-PD-1 therapy in lung adenocarcinoma [ 63 ]. Concurrently, SNS has been shown to promote the activity of regulatory T cells (Tregs) and MDSCs, thereby creating an immunosuppressive TME [ 64 – 66 ]. Together, directly disrupting the balance between anti-tumor immunity and immunosuppressive cells is a key mechanism through which SNS exerts its effects.

In summary, the SNS drives tumor progression by coordinately promoting malignant cell proliferation, angiogenesis, and immune suppression, thereby remodeling the TME into a pro-tumorigenic niche.

Tumor metastasis

Metastasis, the leading cause of cancer-related death, is a highly energy-intensive process that involves extensive cellular changes, including cytoskeletal reorganization, ECM remodeling, and metabolic adaptations. The SNS promotes metastasis via β-AR signaling, wherein NE enhances tumor cell motility and invasion by inducing EMT, upregulating vimentin, downregulating E-cadherin, and stimulating MMP-2/9-mediated ECM degradation [ 21 , 67 – 70 ]. For example, NE has been shown to induce EMT in gastric adenocarcinoma cells via the β2-AR-HIF-1α-Snail signaling axis, revealing a novel stress-related regulatory pathway in tumor progression [ 69 ].

Beyond these structural effects, SNS-driven metabolic adaptations further support metastasis. NE-induced glycolysis increases ATP availability for migration, and chronic stress-induced reprogramming of lipid metabolism has been linked to increased metastatic potential in breast and prostate cancer [ 15 , 71 ]. This is associated with the regulation of lipolytic signaling via the AKT-USP22-FOXO1-ATGL axis, which promotes fatty acid release to fuel metastatic dissemination. Future research should further investigate the interplay between SNS-mediated metabolic shifts and tumor cell metastasis, which may reveal novel metabolic targets for anti-metastatic therapy.

SNS regulation of cellular metabolism in tumor progression

As previously discussed in Section –SNS in tumor progression” , the growth and metastasis of tumors are closely intertwined with the complex regulation of cellular processes such as proliferation, angiogenesis and immune modulation. A crucial aspect of this regulation is the profound metabolic rewiring induced by the SNS, which engages ARs on tumor and stromal cells by releasing neurotransmitters such as NE and E, triggering metabolic shifts that fuel tumor progression and metastatic potential. SNS-triggered metabolic adaptations involve glycolysis, lipid metabolism, and oxidative phosphorylation (OXPHOS), which collectively sustain tumor growth and metastasis [ 15 , 16 , 70 ].

The present section aims to delve into the specific metabolic effects of SNS signaling on the various cellular components within the TME, elucidating how these changes contribute to tumor growth and metastasis.

Tumor cell

One of the most significant metabolic adaptations observed in tumors is the Warburg effect, which has attracted considerable scientific interest due to its implications in various pathological contexts [ 17 ]. SNS activation significantly enhances glycolysis through β-AR signaling, which upregulates glucose transporters such as GLUT1 and activates key enzymes like hexokinase 2 (HK2), phosphofructokinase (PFK) and pyruvate kinase M2 (PKM2) (Figure. 2 ) [ 72 – 75 ]. Accelerated glycolysis in cancer cells diverts glycolytic intermediates into anabolic pathways, supporting the synthesis of macromolecules required for cell proliferation (Figure. 2 A) [ 76 , 77 ]. In the context of gastric cancer, NE has been observed to augment aerobic glycolysis, potentially serving as a prognostic indicator for immunotherapy interventions [ 78 ]. Chronic stress-induced E activates lactate dehydrogenase A (LDHA), promoting lactate production. This, in turn, alters the pH level (Figure. 2 C), facilitating the action of ubiquitin-specific protease 28 (USP28) -mediated deubiquitination and stabilization of MYC, which subsequently activates the SLUG promoter, enhancing the expression of genes associated with breast cancer stem cells (Figure. 2 D) [ 79 ]. Furthermore, the SNS has been demonstrated to regulate systemic metabolic processes, including glucose mobilization from the liver, which enhances glycolytic pathways in tumors, thereby promoting tumor growth and progression through increased energy availability for cancer cells [ 21 ].

Recent studies also indicated a potential link between the activation of the SNS and the regulation of lipid metabolism [ 71 , 80 ]. This finding is particularly relevant as lipid metabolism has been identified as a critical process for tumor survival and progression [ 79 ]. E, a key mediator in the SNS under chronic stress, has been shown to promote lipid metabolism in breast cancer by activating a lipolysis pathway involving ubiquitin-specific peptidase 22 (USP22) and adipose triglyceride lipase (ATGL) [ 71 ]. Interestingly, in breast cancer cells, treatment with E or isoprenaline also induces the formation of lipid droplets, suggesting a dynamic lipid remodeling process in which liberated fatty acids may be recycled or stored to support tumor growth (Fig. 2 ) [ 81 ]. This phenomenon may be mediated through the activation of key transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and sterol regulatory element-binding protein 1 (SREBP1) [ 80 ]. Furthermore, chronic stress has been demonstrated to modify fatty acid metabolism, promoting breast tumor growth through a multifaceted stress-microbiome-metabolite-epigenetic-oncology (SMMEO) axis. Specifically, stress-induced dysbiosis of the gut microbiota modifies the circulating metabolite profile, particularly fatty acids, which act as cofactors for chromatin-modifying enzymes and induce epigenetic alterations in tumor cells that favor tumor progression [ 82 ]. Compared to the well-established role of the SNS in regulating glucose metabolism, its involvement in lipid metabolism remains less well defined. This gap underscores lipid metabolic regulation as a promising direction for future research.

In addition to its role in glycolysis and lipid metabolism, emerging studies have revealed that SNS signaling also profoundly influences mitochondrial function and OXPHOS, unveiling a new dimension of metabolic regulation in tumor cells. β2-AR activation has been shown to enhance mitochondrial respiration in tumor cells, supporting energy-intensive processes such as proliferation, migration, and therapeutic resistance. In head and neck squamous cell carcinoma, for instance, β2-AR signaling promotes mitochondrial oxidative metabolism and contributes to a more aggressive tumor phenotype, while genetic ablation of β2-AR markedly reduces OXPHOS capacity and impairs metastatic potential [ 83 ]. Similarly, stimulation with isoproterenol in colon cancer cells leads to a metabolic shift toward OXPHOS and confers increased survival under chemotherapeutic stress, suggesting that SNS may rewire energy production strategies to promote tumor persistence [ 84 ]. Moreover, β-adrenergic blockade has been demonstrated to suppress mitochondrial membrane potential, reduce ATP production, and inhibit tumor growth, indicating that mitochondrial regulation is a functionally relevant downstream target of SNS in the tumor context [ 50 ]. These findings collectively highlight that mitochondrial metabolism and OXPHOS are emerging as important metabolic axes influenced by SNS activity, warranting further investigation into their contribution to tumor energy homeostasis and vulnerability.

Cumulative evidence highlights the extensive role of the SNS in shaping glucose, lipid, and mitochondrial metabolic pathways to support tumor progression. However, its potential influence on amino acid metabolism, another essential axis of tumor bioenergetics remains unclear and should be prioritized in future research to complete our understanding of SNS-driven metabolic modulation.

Immune cell

In addition to tumor-intrinsic metabolic alteration, SNS signaling also profoundly shapes the metabolic environment of the TME, with significant consequences for immune cell function. The impact of SNS on tumor metabolism extends beyond the tumor cells themselves, affecting the immune cells present within the TME (Figure. 2 E). SNS-induced metabolic changes in tumor cell, particularly the enhanced glycolysis and lactate production, may suppress T cell function by acidifying the microenvironment [ 85 , 86 ]. for example, lactate uptake via MCT11 has been shown to enforce CD8⁺ T cell exhaustion, while its blockade restores T cell activity and improves immunotherapy response [ 85 ]. Moreover, SNS activation has been shown to upregulate GLUT1 expression, thereby conferring a “resource-pirate” phenotype on tumor cells within the TME. These cells have been observed to aggressively deplete glucose and other essential nutrients, thereby creating a competitive environment that impairs the function of tumor-infiltrating immune cells (Figure. 2 E), such as CD8 + T cells and NK cells [ 87 ].

Importantly, SNS activity impairs immune cell function not only indirectly, by driving tumor-intrinsic metabolic competition, but also directly, by reconfiguring immune cell metabolism. The metabolic state of immune cells within the TME is a critical determinant of their anti-tumor capacity [ 88 – 90 ]. Accumulating evidence indicates that SNS signaling induces profound metabolic shifts in immune cells, ultimately reprogramming their activity to support immunosuppression and tumor progression (Table 2 ).

CD8 + T cells play a pivotal role in anti-tumor immunity, yet their function is profoundly suppressed by SNS signaling through both systemic and local mechanisms [ 15 , 105 – 107 ]. The SNS exerts its immunosuppressive effects by modulating T cell metabolism, impairing their ability to sustain effective anti-tumor responses. Chronic stress-induced E release has been shown to disrupt the metabolic fitness of tumor-infiltrating lymphocytes (TILs) in mouse models, leading to a metabolic imbalance that weakens their cytotoxic function [ 108 ]. As a compensatory strategy, β-AR blockade has been shown to restore T cell metabolism, enhancing glycolysis and OXPHOS while promoting the upregulation of costimulatory molecules such as CD28, ultimately improving effector function and anti-tumor activity [ 108 , 109 ]. Beyond systemic effects, intertumoral sympathetic nerve fibers directly suppress CD8⁺ T cell function. NE impairs glycolytic activity, resulting in reduced production of interferon-γ (IFN-γ), a key cytokine for T cell-mediated tumor control. This immunosuppressive effect is mediated via β2-AR signaling, which downregulates GLUT1 expression and compromises glycolytic energy supply during T cell activation [ 105 ]. Further mechanistic insights have shown that β2-AR activation impairs CD8⁺ T cell function by inhibiting TCR and mTORC1 signaling via the cAMP-PKA pathway, leading to reduced glucose uptake, suppressed effector differentiation, and metabolic dysfunction. This disruption drives CD8⁺ T cells toward an exhausted phenotype, characterized by diminished cytokine production and cytotoxicity [ 110 ]. In addition to β2-AR, β1-AR signaling has also been implicated in promoting CD8⁺ T cell exhaustion under conditions of chronic sympathetic activation. Targeting β1-AR, particularly in combination with immune checkpoint blockade, has been shown to partially reverse this exhaustion and restore anti-tumor T cell activity [ 15 , 62 ].

MDSCs have been shown to play a crucial role in immunosuppression within the TME by inhibiting the activity of T cells and NK cells [ 111 ]. There is increasing evidence to suggest that SNS signaling profoundly influences MDSC expansion and metabolic programming, further reinforcing their immunosuppressive function [ 66 , 107 ]. In models of lymphoma and breast cancer, NE has been shown to reorient MDSC metabolism, shifting it away from glycolysis while promoting OXPHOS and FAO [ 66 ]. This metabolic shift is facilitated by the upregulation of CPT1A, a key transporter required for FAO-dependent immunosuppressive activity in MDSCs. Furthermore, NE-driven SNS activation enhances autophagy and arachidonic acid metabolism in MDSCs, thereby increasing the production of prostaglandin E2 (PGE2), a potent mediator of immunosuppression and tumor progression [ 66 ]. Recent studies have further elucidated the role of β2-AR signaling in MDSC metabolic adaptation. Catecholamine stimulation via β2-AR activation has been shown to enhance mitochondrial respiration, ATP production, and glutamine metabolism, promoting MDSC survival and resistance to therapy. Consistent with these findings, inhibition of β2-AR signaling has been shown to compromise the metabolic fitness of MDSCs, leading to impaired mitochondrial function and heightened sensitivity to chemotherapy agents such as doxorubicin [ 107 ].

Beyond CD8 + T cells and MDSCs, SNS signaling also shapes the function of other immune cell populations within the TME [ 35 , 112 – 114 ]. Catecholamine signaling via β-ARs promotes M2 polarization of TAMs and Th2 differentiation, fostering an immunosuppressive environment conducive to tumor progression [ 100 , 115 – 117 ]. Although these effects are functionally relevant, direct metabolic evidence remains limited. For instance, while Tregs rely on FAO and OXPHOS for their suppressive function, the specific metabolic mechanisms by which SNS may enhance Treg expansion remain unclear, with glycogen synthase kinase-3 (GSK-3) signaling being a potential but unconfirmed contributor [ 95 , 118 ]. Similarly, the influences of SNS on DCs, neutrophils, and NK cells has been observed [ 119 – 122 ], but the underlying metabolic pathways remain poorly characterized, highlighting the need for future investigation.

Endothelial cell

In the context of cancer, endothelial cells undergo a metabolic rewiring characterized by enhanced glycolysis, which facilitates the formation of new blood vessels, thereby ensuring the delivery of oxygen and nutrients that support tumor growth and metastasis. This process is concomitant with the establishment of an immunosuppressive environment that contributes to cancer progression [ 123 – 125 ]. SNS activation significantly influences endothelial metabolism through NE released from intertumoral sympathetic nerve fibers, which stimulates β-AR on endothelial cells. This metabolic alteration promotes aerobic glycolysis while suppressing OXPHOS, triggering an angiogenic switch that facilitates tumor angiogenesis and accelerates prostate cancer progression [ 41 ]. Given the ratio of parenchymal to endothelial cells in tumors, it is highly probable that sympathetic signaling in tumor cells will also influences tumor neovascularization. For example, culture supernatants from NE-treated breast cancer cells induce capillary-like tube formation in endothelial cells, possibly through activation of mTOR signaling and upregulation of VEGF [ 56 , 124 , 126 ]. Moreover, SNS-driven tumor metabolism increases the production of lactate, which further enhances endothelial cell proliferation by stimulating glycolytic activity and promoting angiogenesis (Figure. 2 F) [ 127 ]. These findings suggest that SNS activation promotes tumor angiogenesis through a complex regulatory network, involving direct stimulation of endothelial β-ARs and indirect paracrine effects mediated by tumor-derived pro-angiogenic factors and metabolites.

Molecular mechanisms of SNS regulation of cell metabolism

The SNS plays a central role in tumor progression by modulating cellular metabolism through intricate signaling networks. These mechanisms integrate neurotransmitter-receptor interactions, transcriptional and epigenetic regulation, and the interplay between intracellular pathways [ 44 , 128 – 130 ], thereby reshaping the metabolic landscape of tumor and stromal cells.

Neurotransmitter and receptor-mediated signaling pathways

The SNS influences cellular metabolism primarily through the release of neurotransmitters, NE and E, which bind to ARs on target cells. These G-protein-coupled receptor (GPCR) are classified into α1-AR, α2-AR, and β-AR subtypes, each triggering distinct downstream signaling cascades via specific G-proteins (Figure. 3 ) [ 130 , 131 ].

For instance, β-AR activation via NE or E triggers cAMP/PKA signaling (Figure. 3 ), leading to upregulation of glucose transporters (e.g., GLUT1) and glycolytic enzymes (e.g., HK2, PFK1) in colorectal cancer [ 74 , 132 ]. This pathway facilitates short-term metabolic adaptations such as increased glycolysis to meet immediate energy demands. Additionally, hepatocytes undergo α1-AR mediated protein kinase C (PKC) activation and enhance glycogenolysis and gluconeogenesis, leading to increased glucose availability in the bloodstream (Figure. 3 ) [ 133 , 134 ]. The resulting hyperglycemia has been shown to promote the progression of liver cancer by fueling tumor metabolism [ 135 ]. In adipose tissue, β-AR stimulate lipolysis through PKA and MAPK signaling pathways, breaking down triglycerides into free fatty acids, which can fuel the progression of multiple tumor types, such as melanoma [ 136 , 137 ]. Together, these pathways support tumor growth under metabolic stress by providing both rapid and sustained energy sources. Under SNS regulation, tumor cells flexibly adapt to changing metabolic demands by switching between glycolysis for quick energy and lipolysis for long-term energy supply. This metabolic plasticity enables continuous proliferation despite fluctuating nutrient availability.

The α1- and α2-AR contribute to metabolic regulation via distinct yet complementary intracellular signaling pathways (Figure. 3 ), functioning in an antagonistic manner to fine-tune cellular energy balance [ 138 ]. Activation of α1-AR promotes energy mobilization through the phosphatidylinositol (PI) signaling cascade, which elevates intracellular calcium levels and facilitates metabolic processes such as lipolysis and gluconeogenesis [ 139 ]. This signaling enhances the release of free fatty acids via PKC and hormone-sensitive lipase (HSL), providing energy particularly during stress or physical activity [ 139 , 140 ]. In contrast, α2-AR activation inhibits adenylate cyclase (AC) activity, reducing cAMP levels and decreasing protein kinase A (PKA) activity [ 141 , 142 ]. This downregulation decreases glycolysis and lipolysis, conserving energy and resources [ 143 ]. Such regulatory antagonism between α1- and α2-adrenergic signaling is particularly relevant under pathological or stress-related conditions, such as stress responses or insulin resistance, where energy conservation is prioritized. In the TME, α1-AR activation is hypothesized to support tumor cell proliferation promoting energy-generating pathways like lipolysis and gluconeogenesis, meeting the high energy demands of proliferating cells. Conversely, α2-AR activation may promote energy conservation by suppressing AC and reducing intracellular cAMP levels. For instance, in lung cancer, decreased cAMP signaling has been associated with enhanced tumor cell survival under nutrient-deprived conditions [ 144 ]. While direct evidence linking α1/α2-AR metabolic regulation to tumor progression is still emerging, their opposing roles likely represent a dynamic mechanism through which tumor cells adjust metabolic strategies to adapt and survive in fluctuating microenvironments.

Transcription factor activation and epigenetic regulation

SNS signaling enhances its metabolic influences through the activation of transcription factors and epigenetic modifications.

Transcriptional regulation

CREB (cAMP-response element-binding protein) : CREB is a pivotal transcription factor that plays a role in SNS-mediated metabolic regulation under both physiological and pathological conditions, including tumor progression. SNS activation induces CREB phosphorylation through cAMP/PKA signaling, leading to the upregulation of metabolic genes such as GLUT1 and LDHA, thereby enhancing glycolytic capacity [ 145 – 147 ]. In colorectal cancer, E has been shown to activate CREB, driving the expression of glycolytic genes and promoting tumor growth [ 74 ]. SNS-induced CREB phosphorylation occurs rapidly, within minutes of adrenergic stimulation, but this response is transient. However, in conditions of chronic stress, sustained SNS activation engages additional transcriptional regulators, such as Egr-1 and Fra-2, contributing to prolonged metabolic and transcriptional reprogramming in tumors [ 148 ]. While CREB activation by SNS is typically rapid and transient, accumulating evidence suggests a broader and more sustained transcriptional program involving additional factors. For example, SNS signaling has been shown to coordinately activate both CREB and HIF-1α across multiple tumor types (e.g. Prostate Cancer), promoting glycolytic gene expression and angiogenesis through parallel ERK/PKA- and PI3K/AKT-mediated pathways [ 53 , 149 ]. This cooperative transcriptional regulation enhances HIF-1α-mediated shift in glucose metabolism within the TME.

HIF-1α (Hypoxia-Inducible Factor 1-alpha) : HIF-1α plays a key role in tumor cell metabolism by promoting the switch from OXPHOS to glycolysis, a hallmark of the Warburg effect. This restructuring of their metabolic circuitry enhances the tumor’s ability to survive and proliferate, even in a hypoxic and nutrient-poor environment [ 150 ]. NE-induced activation of ARs has been demonstrated to stabilize HIF-1α, further promoting VEGF expression and angiogenesis in tumors. For instance, in prostate and colorectal cancer the activation of both β-AR and α1-AR has been shown to enhance HIF-1α stabilization and angiogenesis in a dose-dependent manner, with β-AR playing a major role [ 151 , 152 ].

STAT3 (Signal Transducer and Activator of Transcription 3) : STAT3 is a well-characterized mediator of cellular transformation and metabolic regulation, particularly in cancer cells, where it drives a metabolic shift toward aerobic glycolysis and modulates mitochondrial function [ 153 ]. NE has been demonstrated to enhance STAT3 activation in both gastric cancer and colorectal cancer (CT26). In gastric cancer, inhibition of β-AR signaling using propranolol has been reported to enhance STAT3 activation while suppressing antiviral factors such as PKR, thereby facilitating oncolytic herpes virus replication and ultimately exerting antitumor effects [ 154 ]. Similarly, in CT26 colorectal cancer cells, NE has been found to increase STAT3 activation, contributing to tumor progression. These findings underscore the pivotal role of NE in STAT3-mediated oncogenic processes across multiple cancer types [ 154 – 156 ].

Epigenetic regulation

To meet heightened energetic and biosynthetic demands, cancer cells undergo profound metabolic remodeling, which is closely intertwined with epigenetic regulation. Key metabolites such as lactate and acetyl-CoA are crucial for histone acetylation and DNA methylation [ 157 – 159 ]. The SNS can modulate the production of these metabolites (e.g., Lactate), thereby affecting the activity of epigenetic enzymes and altering the epigenetic landscape [ 72 , 160 ]. The relationship between metabolism and epigenetics is bidirectional, while metabolic changes can influence epigenetic modifications, epigenetic mechanisms can regulate the expression of metabolic genes vice versa [ 161 ]. Under SNS activation, lactate and acetyl-CoA mediate epigenetic changes such as histone lactation and acetylation, potentially leading to the upregulation of genes associated with tumor adaptability and progression hallmarks that support tumor cell survival in a dynamic microenvironment.

Targeting the SNS in cancer therapy: opportunities and challenges

SNS as a potential target for tumor therapy

The critical role of the SNS in tumor progression, encompassing metabolic remodeling, immunoinvasion, and metastasis, underscores its potential as a therapeutic target. Inhibition of SNS signaling has been shown to disrupt these tumor-supportive networks, offering a promising strategy to enhance cancer treatment outcomes and overcome therapy resistance (Table 3 ) [ 15 , 162 , 163 ].

Preclinical studies have provided robust mechanistic evidence supporting this approach. Prolonged inhibition of β-AR signaling typically using non-selective β-blockers such as propranolol has been shown to suppress glycolysis and reduce lactate accumulation, thereby alleviating acidification of the TME and enhancing its immune responsiveness [ 171 , 174 ]. These metabolic alterations not only constrain tumor growth but also re-sensitize resistant tumors to conventional therapies, including chemotherapy and radiotherapy [ 171 , 173 ]. Notably, a study in a triple-negative breast cancer (TNBC) model by Yasmeen M. Attia et al. [ 175 ] demonstrated that β-AR blockade enhanced chemosensitivity by disrupting key resistance-promoting pathways, including HIF-1α and β-catenin signaling. Collectively, these findings suggest that targeting β-ARs can potentiate anti-tumor effects through both metabolic modulation and therapeutic sensitization in specific tumor contexts.

Clinical evidence further supports the translational potential of this strategy. A retrospective analysis of 77 patients with stage IIIA non-small cell lung cancer (NSCLC) who underwent induction chemoradiotherapy followed by surgery found that β-blocker use was associated with a reduced incidence of distant metastasis and a potential improvement in both overall survival (OS) and distant metastasis-free survival (DMFS) [ 176 ]. In breast cancer, four large-scale retrospective studies involving more than 10,000 breast cancer patients found that propranolol use was associated with enhanced chemotherapy efficacy, along with reduced risks of distant metastasis, cancer recurrence, and cancer-specific mortality [ 177 – 181 ]. In one study involving 53 patients, the use of propranolol was significantly associated with a lower risk of melanoma recurrence, with propranolol users experiencing an approximately 80% reduction in risk [ 169 , 182 ]. Similar associations have also been reported in colorectal and prostate cancers, where β-blocker administration was linked to delayed tumor progression and lower recurrence rates [ 167 , 170 ].

Together, these preclinical and predominantly retrospective clinical findings provide a compelling rationale for integrating SNS-targeted therapies, particularly β-AR antagonists, into multimodal cancer treatment frameworks, though the lack of prospective, biomarker-guided trials remains a key limitation.

Limitations and context-dependent challenges of SNS-targeted therapy

Despite these promising findings, a meta-analysis involving over 6350 patients with various solid cancers revealed no significant impact on overall survival or progression-free survival associated with β-AR blocker usage [ 183 ]. A potential explanation for this discrepancy could be that the efficacy of SNS blockers in cancer treatment is highly context-dependent, influenced by factors such as tumor type, stage, and individual patient characteristics (e.g., chronic stress status) [ 163 , 172 ]. These factors likely interact with several biological and treatment-related variables that impact drug responsiveness.

For instance, tumor type critically determines the expression pattern of β-AR subtypes, which directly influences therapeutic sensitivity: Triple-negative breast cancer and melanoma predominantly express β2-AR [ 184 – 186 ], whereas β1-AR may be more relevant in oral squamous cell carcinoma [ 187 ]. Tumor stage and associated structural abnormalities may further limit efficacy, as systemically administered β-blockers often fail to achieve therapeutically effective concentrations within solid tumors [ 169 ]. This limitation is compounded by physical and physiological barriers, such as abnormal vasculature and elevated interstitial pressure, which hinder intratumoral drug penetration. Individual patient characteristics, including stress level and baseline sympathetic tone, can also influence treatment outcomes. Notably, the role of the SNS is not uniformly tumor-promoting; in certain contexts, such as colorectal and pancreatic cancers, inhibitory effects of SNS signaling have been reported [ 188 , 189 ]. Additionally, inconsistency in the timing of β-blocker administration whether initiated prior to diagnosis, during active treatment, or after recurrence may further contribute to heterogeneity in clinical outcomes.

Failure to account for these layers of variability may underlie the conflicting results observed between retrospective studies and meta-analyses. To improve patient selection and therapeutic precision, profiling β-AR subtype expression within tumor tissues could serve as a predictive biomarker to guide receptor-selective inhibitor use. In parallel, circulating catecholamine levels such as plasma NE and E reflect systemic sympathetic activity and may help identify patients with hyperactivated SNS signaling [ 190 ], who are more likely to benefit from β-AR antagonists. Integrating such systemic indicators with intratumoral receptor profiling could facilitate rational patient stratification and improve clinical trial design. A more personalized approach incorporating subtype-specific AR blockade, guided by tumor biology and patient context, may be required to optimize therapeutic efficacy.

Given concerns that systemic ARs blockers may impair cardiovascular function and cause off-target effects, recent advances in localized or tumor-targeted delivery strategies have garnered increasing attention for improving safety and therapeutic precision [ 191 – 194 ]. For example, Chao Yang et al. [ 191 ] developed a biomimetic nanovaccine co-delivering CpG and propranolol, which enhanced T cell infiltration and reversed the immunosuppressive TME, demonstrating significant translational potential for cancer immunotherapy. Similarly, Jiaqi Qin et al. [ 195 ] employed Escherichia coli -derived outer membrane vesicles functionalized with a nerve-targeting peptide and loaded with the Trk inhibitor Larotrectinib to inhibit tumor-associated nerve signaling, thereby improving chemotherapy outcomes in pancreatic cancer. Emerging evidence suggests that catecholamine signaling via ARs can promote a self-reinforcing loop of tumor progression by enhancing neurotrophic secretion and nerve infiltration. In this context, dual inhibition of neurotrophic signaling and adrenergic receptor activation (such as combining Trk inhibitors with β-blockers) may offer a synergistic approach to disrupt this pathological circuit and improve treatment efficacy [ 169 , 196 ]. In addition to these nanotechnology-based approaches, Renal Denervation (RDN) has emerged as a novel strategy for organ-specific ablation of sympathetic innervation [ 197 ], offering the potential for more targeted and durable modulation of SNS activity in tumor-bearing organs. The integration of SNS-targeted therapy with real-time biomarker monitoring (e.g., GLUT1, VEGF, and lactate levels), and combination with behavioral or pharmacological stress management strategies, represents a multifaceted and personalized approach to overcoming the current limitations of SNS blockade.

Integrative neural circuit modulation: expanding the therapeutic framework

Recent studies highlight that the sympathetic, parasympathetic, and sensory nerves may exert distinct and sometimes opposing effects on tumor progression. For example, in breast and pancreatic cancers, sympathetic nerves facilitate tumor growth via β-AR signaling, whereas vagal (parasympathetic) input can suppress inflammation and metastasis. Sensory nerves, through neuropeptides such as substance P, are also implicated in promoting anti-tumor immunity [ 198 – 200 ]. These divergent effects form a neuro-metabolic-immune regulatory axis within the TME. As such, integrative neuromodulator strategies combining β-blockers with vagal stimulation in select tumor types may enhance therapeutic outcomes by rebalancing neural influences. However, current evidence remains limited and fragmented. To translate these concepts into clinical application, future research must go beyond preliminary findings to systematically elucidate the coordinated, spatiotemporal roles of sympathetic, parasympathetic, and sensory circuits-and their collective influences on tumor metabolism and immune dynamics.

Conclusions and future directions

The SNS has emerged as a critical regulator of tumor metabolism, immune evasion, angiogenesis, and metastatic progression. By modulating glucose, lipid metabolism and reprogramming immune cell function within the TME, SNS signaling contributes significantly to cancer progression and therapeutic resistance [ 16 , 38 , 60 ]. Notably, SNS activation promotes glycolysis and lactate production in tumor cells while suppressing glycolytic metabolism in effector T cells, creating a metabolically hostile microenvironment that favors tumor growth and immune escape [ 73 , 74 , 91 , 105 ]. This dichotomous metabolic regulation is likely driven by cell type specific ARs expression and divergent downstream signaling cascades [ 201 – 203 ].

Therapeutically, SNS-targeted interventions, particularly β-blockers offer a promising strategy to disrupt these tumor-supportive pathways. Preclinical and clinical studies have shown encouraging results in restraining tumor progression and enhancing response to chemotherapy and immunotherapy [ 164 – 167 , 175 ]. However, the efficacy of such approaches appears to be context-dependent, influenced by tumor type, ARs subtype expression profiles, and stress-related systemic effects [ 169 , 204 – 206 ]. To address these sources of variability, patient stratification based on ARs subtype expression and metabolic biomarkers along with further clarification of the relationship between specific AR subtypes and key metabolic indicators (e.g., GLUT1, VEGF, lactate levels) may help refine SNS-targeted treatments and enhance therapeutic precision.

Challenges remain. Tumor heterogeneity, compensatory signaling pathways (e.g., PI3K/Akt, MAPK), and the systemic impact of chronic stress can limit the effectiveness of SNS blockade [ 207 , 208 ]. Moreover, the non-specificity and potential side effects of systemic β-blockers highlight the need for more precise delivery strategies. Innovations such as nerve-targeted nanocarriers, combined neuro-immune modulation (e.g., β-blockers with checkpoint inhibitors), and localized sympathectomy have shown potential in overcoming these limitations. Among them, localized sympathectomy achieved through precise surgical techniques (e.g., RDN), represents a promising direction. However, clinical and preclinical evidence supporting the application of RDN in cancer therapy remains limited, highlighting the need for further investigation.

Future directions should aim to map the full spectrum of SNS influences on metabolic and immune networks across diverse tumor types and characterize the impact of AR subtype-specific signaling—particularly β1- and β2-adrenergic receptors—across distinct cellular populations. Integrating SNS blockade into precision oncology through biomarker-guided stratification, stress management, and advanced delivery technologies may help overcome tumor heterogeneity and resistance. Combination approaches, particularly those coupling β-AR inhibition with immunotherapies such as checkpoint blockade, offer promising potential to simultaneously disrupt tumor metabolism and reverse immune suppression. These avenues warrant continued exploration to realize the full therapeutic potential of SNS modulation in cancer treatment.

Acknowledgements

The authors would like to express their sincere gratitude to Dr. Tianlang Pan from ETH Zurich and Dr. Yuxin Qian from Nanjing Medical University for their valuable assistance in polishing the English language of this manuscript.

Abbreviations

Tumor microenvironment

Sympathetic nervous system

Norepinephrine

Glucose transporter 1

Adrenergic receptors

Cancer-associated fibroblasts

Extracellular matrix

Fatty acid oxidation

Epinephrine

Tumor-associated macrophages

Vascular endothelial growth factor

Myeloid-derived suppressor cells

Neuroendocrine prostate carcinoma

Sympathetic-adrenal-medullary

Natural killer

Regulatory T cells

Epithelial-mesenchymal transition

Hexokinase 2

Phosphofructokinase

Pyruvate kinase

Lactate dehydrogenase A

Ubiquitin-specific protease 28

Ubiquitin-specific peptidase 22

Peroxisome proliferator-activated receptor gamma

Sterol regulatory element-binding protein 1

Stress-microbiome-metabolite-epigenetic-oncology

Oxidative phosphorylation

Oxidative pentose phosphate pathway

Tumor-infiltrating lymphocytes

Prostaglandin E2

Helper T cells

Glycogen synthase kinase-3

Dendritic cells

G-protein-coupled receptor

Phospholipase C

Adenylyl cyclase

Protein kinase C

Hormone-sensitive lipase

Phosphatidylinositol

Protein kinase A

cAMP-response element-binding protein

Hypoxia-Inducible Factor 1-alpha

Signal Transducer and Activator of Transcription 3

Transvascular Renal Denervation

Hypothalamic-pituitary-adrenal

Author contributions

All authors participated in the research and writing of the manuscript, and Jianqiong Zhang made key revisions to the knowledge of the paper.

Funding

Chinese Scientific and Technological Innovation 2030: STI2030-Major Projects-2021ZD0204000.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s note

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

Chen Sun and Yuqing Shen contributed equally to this work.

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Associated Data

Data Availability Statement

Not applicable.