A malignant symbiosis: The neuro-metabolic symphony rewires the tumor microenvironment.

Introduction

Malignant tumorigenesis, an intricate pathophysiological process, is governed by intrinsic genetic aberrations within tumor cells and their dependence on the surrounding tumor microenvironment (TME) [ 1 ]. This ecosystem comprises neoplastic cells, stromal fibroblasts, immune infiltrates, vasculature, and extracellular matrix [ 2 ]. Metabolic reprogramming has recently been established as a hallmark of cancers. To adapt to hostile microenvironmental conditions characterized by hypoxia and nutrient deprivation, tumor cells rewire fundamental pathways, including glycolysis, lipid metabolism, and amino acid turnover, thereby securing the energetic and biosynthetic precursors necessary for rapid proliferation [ 3 , 4 ]. While current research has extensively characterized the metabolic interplay between tumor and immune cells [ 5 , 6 ], the nervous system, an ubiquitous and potent regulator within the TME, has received limited attention. Emerging evidence from cancer neuroscience research indicates that tumor tissues are not merely passively innervated; they engage in active bidirectional signaling with neurons [ 7 ]. The nervous system supports tumor survival and releases neurochemical mediators, such as neurotransmitters, neuropeptides, and hormones. These neural-derived mediators form a multilayered signaling network with tumor, immune, and stromal cells, which drives local metabolic reprogramming and profoundly affects tumor initiation, progression, and therapeutic resistance [ [8] , [9] , [10] , [11] ].

While Wang et al. [ 12 ] delineated the general modes of tumor-neural communication and Liu et al. [ 13 ] surveyed therapeutic targeting strategies, our review uniquely focuses on the metabolic dimension - we key dissect how neural signals act as a 'conductor' to reprogramme specific metabolic fluxes (glycolysis, fatty acid oxidation (FAO), glutaminolysis) in both cancer and stromal cells, thereby closing a malignant feedback loop. First, we delineated the signaling axes governed by peripheral afferent and efferent fibers, along with the locally secreted neuromodulators. These encompass catecholaminergic signaling driven by the sympatho-adrenal axis, cholinergic networks orchestrated by parasympathetic innervation and tumor autocrine loops, and the release of neuropeptides from sensory nerves. By ligating specific receptors in the neoplastic and stromal compartments, these transmitters transduce downstream cascades that orchestrate microenvironmental metabolic reprogramming and stromal rewiring. Second, recognizing that local neurotransmitter concentrations undergo profound shifts during pathological or stress states, we scrutinized the specific impacts of amino acids (e.g., glutamate and gamma-aminobutyric acid (GABA)) and monoaminergic (e.g., serotonin (5-HT) and dopamine (DA)) transmitters. We examined how these molecules dictate critical metabolic shifts within both malignant cells and infiltrating immune populations via receptor-dependent signaling cascades. Third, we analyzed the systemic impact of the neuroendocrine axis, detailing how the regulation of glucocorticoids, thyroid hormones, and melatonin shapes a pro- or antitumor metabolic niche, which in turn affects metastasis and drug resistance. Fourth, we explored the reverse signaling paradigm, in which tumor-derived metabolites (e.g., lactate, mutant isocitrate dehydrogenase (IDH) oncometabolites, lipids, nucleotide metabolites, adenosine, and tryptophan derivatives) accumulate in the TME and modulate the excitability and function of adjacent nerve fibers. Furthermore, we outline the severe clinical sequelae of this metabolic crosstalk, including cancer-associated pain, depression, and cachexia. Finally, we link mechanistic insights to clinical perspectives, elucidating how the nervous system reprograms the metabolic network to drive therapeutic resistance and identifying targeting of the neuro-metabolic axis as a novel precision oncology strategy.

Neural signaling orchestrates metabolic reprogramming in the TME

Catecholamine signaling (sympathetic nerves + adrenal epinephrine)

Catecholamine signaling, including norepinephrine (NE) and epinephrine (EPI) signaling, promotes the energetic reprogramming of tumor cells by aberrantly activating glycolysis and lipolysis pathways. It also remodels the immunosuppressive microenvironment, directly driving stress-adaptive tumor growth and systemic metabolic dysfunction [ 14 ] ( Fig. 1 ).

Tumor cells hijack clinical studies, revealing that NE released by the sympathetic nervous system and EPI secreted by the adrenal glands alter substrate utilization patterns to meet the energy demands of malignant proliferation. At the molecular level, adrenergic receptor stimulation triggers kinase cascades that comprehensively upregulate the expression of metabolic enzymes. In prostate cancer, stress-induced NE stimulates the PKA pathway and the phosphorylation of the transcriptional regulator cAMP Response Element-Binding Protein (CREB) via β2-adrenergic receptors (ADRB2) [ 15 ]. Upon ADRB2 activation, CREB1 upregulates membrane-localized glycolytic enzymes in colorectal cancer (CRC) (e.g., GLUT1, HK2, and PFKP), thereby fuelling tumor cell proliferation [ 15 , 16 ]. In gastric cancer, the reduced expression of monoamine oxidases (monoamine oxidase A (MAOA) / monoamine oxidase B (MAOB))—enzymes responsible for NE degradation-leads to local NE accumulation, which potentiates glycolytic activity in tumor cells [ 17 ]. In addition to the aberrant activation of glycolysis, elevated local EPI levels in pheochromocytoma directly accelerate the tricarboxylic acid (TCA) cycle. This induces a diagnostically significant metabolite rearrangement, characterized by a marked increase in citrate and depletion of fumarate and malate [ 18 ].

This metabolic remodeling also extends to the lipid metabolism. Breast cancer cells utilize the EPI-USP22-ATGL lipolytic axis to accelerate lipolysis by deubiquitinating and stabilizing adipose triglyceride lipase (ATGL), thereby providing an abundance of free fatty acids to support tumor invasion and metastasis [ 19 ]. These findings establish that NE and EPI act as core catalysts in the reprogrammed metabolic networks of tumors. Blocking adrenergic-driven glycolysis and lipid metabolism has emerged as an effective strategy to cut off the energy supply required for tumor proliferation, invasion, and metastasis.

In addition to regulating the intrinsic metabolism of tumor cells, catecholamine signaling remodels the biological functions of stromal and immune cells through specific metabolic reprogramming cascades. Within the immune microenvironment, ADRB2 signaling directly upregulates the fatty acid transporter carnitine palmitoyltransferase 1A (CPT1A). This enhances the FAO capacity of myelooid-derived suppressor cells (MDSCs), thereby creating a localized metabolic barrier [ 20 ]. Similarly, MAOA downregulation is accompanied by an increase in immune checkpoint components, such as PD-L1, which further reinforces immune tolerance [ 21 ]. Regarding stromal remodeling, Luo et al. [ 22 ] demonstrated that paracrine NE activates hepatic stellate cells via the SRC/AKT/ERK pathway, consequently altering the stromal microenvironment in hepatocellular carcinoma (HCC). Furthermore, this stress network is not confined to the local tumor bed and perturbs systemic homeostasis. For instance, ubiquitin-specific protease 2 (USP2) in the ventromedial hypothalamus alters systemic glucose homeostasis via the ROS/AMPK pathway, which may influence tumor metabolic adaptability by shifting glucose metabolism patterns within the TME [ 23 ]. Therefore, the neuro-metabolic regulatory network tightly integrates metabolic reprogramming, stromal activation, and local immune evasion.

Although catecholamines generally exhibit pro-tumorigenic metabolic traits, their net effect is highly dependent on the composition of receptor subtypes, which can play divergent or even contradictory roles in tumor metabolism. On the one hand, classical β-receptors (β2, β3) primarily drive pro-tumor metabolism. Beyond the aforementioned β2-driven glycolysis, β3 receptors not only promote glutathione synthesis to protect tumors from microenvironmental oxidative stress-induced death [ 24 ] but also drive the pathological remodeling of systemic adipose tissue (lipid dysmetabolism) in cancer cachexia [ 25 ]. In contrast, the α2A-adrenergic receptor (ADRA2A) is a definitive tumor suppressor in pancreatic ductal adenocarcinoma.Its downregulation is associated with enhanced tumor aggressiveness, increased lymph node metastasis, and decreased patient survival [ 26 ].

The mechanism underlying this paradox is that while the β-receptor family predominantly couples to stimulatory networks (e.g., lipolysis and glycolysis), the α2A subtype blocks anabolism in specific tissues by inhibiting intracellular cyclic AMP (cAMP) accumulation. This complexity is also reflected in clinical pharmacology. For example, duloxetine, an antidepressant and NE reuptake inhibitor, increases synaptic NE concentrations and, under certain conditions, promotes HCC cell migration via the c-Jun N-terminal kinase (JNK) pathway [ 27 ]. This highlights the clinical necessity of avoiding non-selective (pan-adrenergic) interventions, as non-specific drugs may inadvertently activate pro-tumorigenic receptor subtypes.

Targeted interventions focusing on catecholamine anabolic pathways and their receptor specificities offer viable clinical strategies for reversing the metabolic advantages of tumors. In precision diagnostics, the promoter methylation levels of catecholamine-synthesizing genes (e.g., tyrosine hydroxylase, dopamine β-hydroxylase, and phenylethanolamine N-methyltransferase) directly dictate the metabolic phenotype (MN/NMN secretion patterns) of pheochromocytoma [ 28 ]. This underscores the critical importance of combined metabolomic and epigenetic monitoring in clinical settings [ 29 , 30 ]. Researchers have leveraged neuro-metabolic pathways to develop novel therapeutic tools. Lyu et al. [ 31 ]engineered a polydopamine-NE nanoplatform that converted NE into a delivery vector, transporting drugs directly into the mitochondria to trigger ferroptosis and eliminate tumor cells. The natural product ginsenoside Rb1 has been shown to inhibit glycolysis and tumor growth by blocking the β2-AR/CREB1 axis [ 32 ]. Moreover, the classic herbal formula Sini San modulates the stress response of HCC via the brain-gut-tumor axis, systematically restricting tumor growth by enhancing gut microbiota diversity [ 33 ]. The traditional formulation Sini Powder alleviates stress responses in HCC and systemically inhibits tumor progression by restoring gut microbiota diversity via the neuro-gut-tumor metabolic axis [ 34 ]. Additionally, β-blockers have been found to directly impair mitochondrial bioenergetics, abolishing the tumor's capacity for metabolic remodeling and thereby significantly increasing its radiosensitivity [ 35 ]. These translational findings confirm that targeting specific adrenergic receptor subtypes in combination with cellular metabolic inhibitors to sever the nerve-driven energy supply is a core approach for remodeling the TME.

In conclusion, catecholamine signaling via the sympathetic nervous system and adrenal glands acts as a systemic master regulator of TME metabolism and whole-body energy homeostasis. It directly mediates glycolipid metabolism and immune evasion in tumor cells through specific receptor subtypes. Future clinical interventions must bypass non-specific neuromodulation and adopt combinatorial strategies that utilize selective antagonists against oncogenic receptor subtypes, alongside inhibitors of glycolysis, mitochondrial function, or lipid synthesis. Such approaches will not only dismantle the localized metabolic niche of the tumor but also effectively reverse systemic cachexia in patients.

Cholinergic signaling (parasympathetic + autocrine ACh)

Cholinergic signaling reprograms the energetic networks of tumor cells in a receptor subtype-specific manner. Specifically, nicotinic acetylcholine receptors (nAChRs) drive metabolic compensation under hypoxia and oxidative stress, whereas muscarinic acetylcholine receptors (mAChRs) exert a braking effect by modulating mitochondrial activity and the energetic demands of the cell cycle [ 36 ] ( Fig. 2 ).

Tumor cells primarily utilize nAChR-mediated pathways to sense the metabolic microenvironment and initiate energetic compensatory mechanisms in response to hypoxic and toxic stress. Upon parasympathetic stimulation, tumor cells acquire the ability to synthesize and secrete acetylcholine (ACh) by expressing choline acetyltransferase. This autocrine ACh activates α7-nAChRs, leading to elevated levels of protein kinase D1, which directly enhances the stability of hypoxia-inducible factor 1α (HIF-1α). Given that HIF-1α is a master regulator of glycolytic reprogramming, this indicates that cholinergic signaling directly triggers the Warburg effect to help maintain adenosine triphosphate (ATP) supply under hypoxic conditions [ 37 ]. In addition to responding to internal stress, nAChRs function as sensors of extracellular metabolites and toxins. In glioblastoma, choline, a precursor metabolite of membrane phospholipids, acts as an endogenous agonist that directly activates α7/α9-nAChRs. This allows tumor cells to sense local metabolite concentrations and alter their proliferative dynamics [ 38 ]. Proliferative signaling also depends on metabolic mediators such as calcium. Choline or nicotine can activate α7-nAChRs to trigger a calcium (Ca 2+ ) signaling cascade, thereby driving breast cancer cell proliferation [ 39 ]. Furthermore, exogenous substances (e.g., nicotine and the tobacco-specific carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)) remodel metabolism via this system. In head and neck squamous cell carcinoma (HNSCC), nicotine specifically activates α5-nAChRs to upregulate the metabolic enzyme carboxylesterase 1 (CES1), promoting tumor recurrence and metastasis [ 40 ]. In lung cancer, NNK aberrantly activates the local renin-angiotensin system (RAS) via the nAChR/SRC/STAT3 pathway, inducing a malignant transition in tumor metabolism and angiogenesis [ 41 ]. Conversely, when environmental toxins reduce nAChR activity in neuroblastoma (SH-SY5Y cells), the levels of glutathione (GSH) and antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) within the cellular defense system decline, triggering severe reactive oxygen species (ROS) accumulation [ 42 ]. Thus, whether through exogenous activation or autocrine regulation, nAChRs constitute a critical defense line for tumor cells to resist metabolic crises and maintain energy balance and redox homeostasis in the TME.

In contrast to the universally pro-tumorigenic and energy-compensating functions of nAChRs, mAChRs exhibit highly complex regulatory roles in metabolism and metabolic braking within the TME. This functional divergence between receptor families dictates the pleiotropic nature of the cholinergic signaling. In glioblastoma, the activation of M2-mAChR variants does not promote proliferation; rather, it disrupts normal mitotic spindle assembly, driving cells into cell cycle arrest [ 43 ]. Similarly, the predominant M1R subtype in neuroblastoma has an inhibitory effect on mitochondrial respiration. Only when M1R activity is blocked by antagonists, the cellular energy sensor AMP-activated protein kinase (AMPK) is activated, which subsequently restores mitochondrial activity and respiratory chain function [ 44 ]. In addition, mAChR expression is strictly governed by metabolic epigenetics. In HNSCC, mAChR expression patterns are regulated by methylation within the epigenetic landscape, which affects the tumor metabolic microenvironment and choline-induced obesity [ 45 ]. Based on these functions, nAChRs primarily act as pro-survival switches under stress conditions, driving glycolysis and antioxidant defense. In contrast, mAChRs modulate organelle activity and energy allocation. Hyperactivation can induce mitochondrial stress or cell cycle arrest, thereby suppressing tumor proliferation in specific contexts.

Given the distinct roles of cholinergic receptor subtypes in energy metabolism, precisely evaluating receptor status and employing combinatorial metabolic inhibitor strategies have emerged as new paradigms for disrupting the survival advantages of tumors. The development of positron emission tomography (PET) imaging probes has enabled noninvasive in vivo assessment of cholinergic receptor status and drug occupancy, thereby guiding targeted metabolic interventions [ 46 ]. Based on the aforementioned core role of nAChRs in maintaining energy supply, preclinical studies have tested combination therapies targeting the putative nicotine-cholinergic pathway in esophageal squamous cell carcinoma. The results demonstrated that blocking the receptors with nAChR inhibitors, such as dextromethorphan, combined with metformin, a traditional metabolic modulator that inhibits mitochondrial complex I, yields a highly synergistic antitumor response [ 47 ]. This indicates that directly blocking nAChRs to abolish their anabolic effects, superimposed with mitochondrial energy deprivation, can thoroughly dismantle the metabolic defense systems of smoking- or hypoxia-associated tumors.

Cholinergic signaling is not a monolithic pro-tumorigenic driver; rather, it operates as a receptor-dependent metabolic modulator. In clinical settings, the use of non-selective pan-cholinergic blockers should be avoided. Utilizing nAChR-specific antagonists combined with mitochondrial/glycolysis inhibitors, or leveraging mAChRs to intervene in mitochondrial and cell cycle dynamics, represents the key to successful metabolic therapy for cancer. Precisely identifying and blocking the specific receptor pathways that mediate survival dependency is essential for the development of future therapies.

Sensory neuropeptides

Within the TME, sensory nerves have been re-conceptualized beyond their traditional role as conduits for nociceptive signaling. Neuropeptides are now recognized as potent metabolic modulators. Sensory nerve terminals secrete neuropeptides, such as substance P and neurotensin, which engage G protein-coupled receptors (GPCRs) on neoplastic and stromal cells to directly rewire intracellular metabolic networks [ 36 ]. The metabolic impact of these neuropeptides is twofold: they drive lipid mobilization (via fatty acid oxidation) to engineer an immunosuppressive niche and recalibrate calcium and mitochondrial dynamics to meet the energetic demands of malignant proliferation.

Sensory neuropeptide signaling acts as a master switch that governs systemic lipid allocation and local immune checkpoint functions. Systemically, neuropeptides released from sensory nerve terminals, such as pathways involving neurokinin-3 receptor (NK3R) blockade, prompt adipose tissue to transition from a "storage mode" to an "oxidative mode," triggering a reduction in fat mass and adipocyte atrophy [ 48 ]. This systemic lipid mobilization supplies tumors with a continuous influx of energetic substrate. Within the local TME, this altered lipid metabolism is hijacked to induce immunosuppression in the tumor microenvironment. In CRC, for example, the aberrant expression of the melanocortin 1 receptor (MC1R) drives regulatory T cells (Tregs) toward FAO through metabolic reprogramming. Given the profound reliance of Treg function on FAO, MC1R effectively operates as a metabolic toggle, fostering immune tolerance by dictating lipid utilization [ 49 ]. Yang et al. further corroborated that lipid metabolism-related gene signatures can precisely predict immune evasion driven by neuroendocrine signaling in CRC [ 50 ]. Consequently, through lipid reprogramming, sensory neuropeptides not only sustain tumor anabolism but also synergistically drive local immune evasion and host metabolic exhaustion. Intracellularly, sensory neuropeptides secure the bioenergetic supply of tumor cells within high-stress microenvironments by precisely modulating calcium homeostasis and mitochondrial dynamics. The signaling cascades of sensory neuropeptides converge on the Sigma-1 receptor, which directly maintains the activity of mitochondrial oxidative phosphorylation by regulating Ca 2+ flux between the endoplasmic reticulum and mitochondria [ 51 ]. Because calcium homeostasis is tightly coupled with the efficiency of the TCA cycle, neuropeptide-mediated tuning of Ca 2+ flux directly dictates the ATP production rate in tumor cells. This indicates that sensory neural signals can be directly transduced into intracellular metabolic momentum, thereby satisfying the exceptionally high energy thresholds required for malignant proliferation.

From a translational medicine perspective, exploiting the metabolic trapping characteristics of neuropeptide receptors for targeted intervention represents a critical pathway for overcoming therapeutic bottlenecks in highly aggressive tumors. Studies focusing on the neurotensin receptor 1 (NTSR1) axis have revealed its overexpression in highly malignant tumors, such as pancreatic cancer [ 52 ]. It not only accelerates cancer progression but also provides an avenue for in vivo imaging. The significant retention of radiotracers in regions with high NTSR1 expression confirms the feasibility of receptor-mediated metabolic imaging for precision diagnostics [ 53 , 54 ]. A parallel mechanism exists in small cell lung cancer; the clinical significance of antagonists developed against the neuroendocrine receptor NK1R lies not only in inhibiting tumor growth by severing energetic pathways but also in reversing microenvironmental immunosuppression by disrupting the metabolic axis [ 55 , 56 ]. Currently, clinical research should focus on developing high-affinity GPCR antagonists coupled with receptor-directed radionuclide imaging to achieve multidimensional precision targeting of the nerve-metabolism-immunity axis.

Ultimately, sensory neuropeptides have evolved from being mere nociceptive messengers to systemic coordinators of tumor metabolism. By blocking key receptors, such as NK3R or NTSR1, clinicians can achieve a dual-pronged therapeutic effect: curbing systemic lipid mobilization to mitigate cachexia while simultaneously dismantling the localized calcium-mitochondrial metabolic coupling to restore immune surveillance.

Amino acid neurotransmitters (glutamate, GABA)

Glutamate

As a key metabolite in the TME, glutamate, along with glutamine, functions as an excitatory neurotransmitter in the central nervous system. Under metabolic stress, hypoxia, and nutrient deprivation, tumor cells rapidly and continuously rewire their metabolic pathways toward glutamine/glutamate to facilitate their adaptive growth. This metabolic reprogramming acts as a primary driver of cancer hallmarks and progression, encompassing energy production, biosynthetic pathways, redox balance, angiogenesis, and TME remodeling [ 57 ]. Consequently, the glutamate and glutamine metabolic axis dictates GSH-dependent redox adaptation in tumors and promotes microenvironmental immunosuppression and distant metastasis by remodeling the stromal vasculature and immune cell phenotypes ( Fig. 3 ).

Intracellularly, tumors reprogram the glutamate/glutamine pathway via epigenetic and transcriptional regulation, serving as a core metabolic survival mechanism against extreme nutrient deprivation and oxidative stress [ 58 ]. Solid tumors, such as prostate cancer, heavily rely on this pathway to synthesize ATP and pro-tumorigenic metabolites [ 59 ]. Glutaminase 1 (GLS1) plays a crucial role in this process. Rather than directing glutamate into the canonical TCA cycle for energy, it specifically channels glutamate as a critical substrate for GSH synthesis in the mitochondria. Blocking GLS1 directly depletes GSH, triggers ROS accumulation, and induces the degradation of the antioxidant enzyme glutathione peroxidase 4 (GPX4), ultimately causing tumor cells to undergo ferroptosis [ 60 ]. Cellular acquisition of glutamate is stringently regulated by multi-tiered mechanisms. This includes the dysregulation of the dicarboxylic amino acid transporter solute carrier family 1 member 1 (SLC1A1) in clear cell renal cell carcinoma [ 61 ], and the post-transcriptional control of the glutamate dehydrogenase 1 (GLUD1) and solute carrier family 1 member 5 (SLC1A5) enzymes by the long non-coding RNA HOX transcript antisense intergenic RNA in CRC, which influences glutamate production to fuel tumor progression [ 62 ]. Thus, hijacking the glutamate metabolic network is a basal defense strategy for tumor cells to maintain redox homeostasis and avert metabolic collapse in hostile microenvironments.

Beyond intracellular bioenergetics, extracellularly released glutamate acts as a potent paracrine signal that directly reshapes the immune, vascular, and metastatic microenvironments of tumors. Immunologically, elevated glutamate levels in hepatocellular carcinoma activate the N-methyl-D-aspartate receptor subunit 2B (NMDAR2B) receptor, which suppresses enhancer of zeste homolog 2 (EZH2)-mediated histone methylation and subsequently induces C—C motif chemokine ligand 2 (CCL2) release. This recruits pro-tumorigenic macrophages, forming an immunosuppressive niche [ 63 ]. Regarding vascular and stromal remodeling, gliomas utilize glutamine synthetase to alter blood-brain barrier (BBB) permeability and induce aberrant angiogenesis [ 64 ]. Concurrently, they rely on the metabolic enzyme sirtuin 4 (SIRT4) to deacetylate and stabilize the glutamate transporter glial high affinity glutamate transporter 1 (GLT-1), thereby preventing excitotoxicity from backfiring on the tumor itself [ 65 ]. This glutamate-mediated stromal remodeling directly precipitates distant metastasis. In breast cancer brain metastasis models, glutamate synergizes with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway to elevate interleukin 8 (IL-8) and growth-related oncogene levels, disrupting the BBB and activating astrocytes [ 66 ]. Simultaneously, exosomes released by breast cancer cells carry glutamate-sensitive proteins that inhibit the mitogen-activated protein kinase (MAPK) pathway in target cells, paving the way for brain colonization [ 67 ]. This demonstrates that secretory glutamate is not merely a metabolic byproduct; it is a pioneer molecule that enables tumors to breach tissue barriers and remodel the stroma of distant target organs.

Translationally, precise interventions targeting the glutamate metabolic axis and associated protein structural repair offer highly safe therapeutic options. Knocking out the cystine/glutamate antiporter xCT solute carrier family 7 member 11 (SLC7A11) has been proven to significantly impairs the metastatic routes of breast cancer without compromising the host's systemic immune function [ 68 ]. Even more at the forefront, given that glutamate mutations into nonsense stop codons inactivate numerous tumor suppressor proteins, a newly developed engineered glutamate tRNA (tRNAGluV13) can forcefully insert glutamate at premature termination codons This technology has successfully restored the function of inactivated tumor suppressors in hereditary breast and ovarian cancer models [ 69 ]. Combinatorial interventions targeting the glutamate axis (e.g., dual inhibition of GLS1 and GPX4 to trigger ferroptosis), alongside the utilization of engineered tRNAs to repair mutations, represent effective precision strategies to dismantle the tumor's redox defense system and reconstruct a tumor-suppressive environment at the genetic level.

GABA

GABA, the principal inhibitory neurotransmitter in the central nervous system, drives cell cycle progression and malignant colonization in tumors through receptor-mediated oncogenic signaling cascades and intracellular accumulation of metabolites [ 70 ]. However, its net effect is highly dependent on local concentration and microenvironment. Consequently, GABA exerts highly context-specific functions, and its promotion or suppression of tumor growth varies according to the cancer type, receptor subtype, and associated signaling pathways ( Fig. 3 ).

Under most natural pathological conditions, endogenous GABA signaling drives tumor anabolism and malignant proliferation, primarily through specific receptor networks and lipid compartmentalization. By activating GABA-B receptors, GABA modulates the ERK1/2 pathway and upregulates the glycolytic enzyme glutamate decarboxylase 1 (GAD1) in multiple myeloma, thereby promoting tumor cell proliferation [ 71 ]. In CRC, it inhibits the proteasomal degradation of MYC proto-oncogene, cellular (c-Myc), stabilizing this transcription factor to accelerate epithelial-mesenchymal transition (EMT) [ 72 ]. Conversely, GABA-A receptors in gliomas promote EZH2 palmitoylation via the Src pathway, thereby reinforcing cancer stem cell characteristics [ 73 ]. In addition to receptor-mediated routes, aberrant intracellular accumulation of GABA is equally pro-tumorigenic. In brain metastases from non-small cell lung cancer, loss of the transcription factor forkhead box A2 (FOXA2) inactivates the GABA-catabolizing enzyme GABA-T. This leads to massive intracellular GABA accumulation, which ultimately stimulates the NF-κB pathway and provides critical biosynthetic precursors for tumor colonization within the brain microenvironment [ 74 ]. Furthermore, chronic GABA stimulation can perturb the GABA transporter 3 (GAT3) and lipid raft-associated plasma membrane Ca 2+ -ATPase 4 (PMCA4) complex in gliomas, triggering calcium overload and inducing invasion [ 75 ]. Thus, tumor cells not only hijack membrane-bound GABA receptors to stabilize oncoproteins but also exploit the metabolic accumulation resulting from impaired GABA degradation to satisfy the biosynthetic demands of malignant tumors.

Although endogenous GABA broadly exhibits pro-tumorigenic metabolic functions, it can elicit a starkly contrasting tumor-suppressive effect under specific exogenous interventions. For instance, in therapeutic studies of oral squamous cell carcinoma, delivering high doses of GABA locally to the tumor via nanocarrier systems did not promote growth; instead, it significantly downregulated GSH levels. This triggers oxidative stress and ultimately leads to CCND2-mediated apoptosis [ 76 ]. The underlying mechanism of this seemingly paradoxical outcome can be explained by the concentration gradients and metabolic buffering thresholds. Tumor cells rely on physiological concentrations of GABA in their microenvironment for signal transduction and oncogenic reprogramming. However, a sudden influx of high-concentration exogenous GABA completely disrupts the cell's baseline amino acid metabolic equilibrium, depleting critical molecules (e.g., GSH) that are required to maintain redox homeostasis. This effectively converts pro-survival signals into growth-inhibitory signals. This finding reveals that the metabolic effects of GABA are not immutable; rather, they are co-determined by the inherent metabolic baseline of the tumor and the localized concentration gradient of free GABA.

Because tumors heavily depend on physiological concentrations of GABA signaling to sustain their malignant proliferation networks, implementing polarized intervention strategies in precision oncology, either by developing specific antagonists to block oncogenic GABA receptors or utilizing nanocarriers to deliberately induce localized GABA overload until cells succumb to oxidative stress collapse, will serve as an effective paradigm for dismantling this neuro-metabolic axis.

Monoamine neurotransmitters (5-HT, dopamine)

5-HT

5-HT does not act directly as a bioenergetic substrate for tumor cells; rather, it functions as an anabolic signal initiator. By driving kinase cascades and rewiring nucleotide metabolism, 5-HT endows tumors with a survival advantage to withstand hostile microenvironments and antimetabolite therapies [ 77 ].

Primarily, 5-HT transduces extracellular stress signals into intracellular pro-survival anabolic processes via the plasma membrane receptors. In CRC, 5-HT specifically activates the 5-Hydroxytryptamine receptor 2B (HTR2B), maintaining sustained phosphorylation of the downstream MAPK/ERK pathway [ 78 ]. Similarly, the environmental endocrine disruptor bisphenol A triggers the ERK pathway by activating the 5-HT3 receptor, thereby driving EMT [ 79 ]. Pharmacological blockade of HTR2B using targeted agents, such as SB204741 or GM-60186, completely severs this kinase cascade and significantly halts tumor proliferation and migration [ 78 ]. This confirms that the receptor-kinase axis is the core route through which tumor cells initiate metabolic adaptation within the microenvironment.

Beyond kinase pathways, 5-HT reorganizes intracellular nucleotide metabolic homeostasis via second messenger systems, directly dictating tumor chemosensitivity and chemoresistance. Overexpression of the 5-Hydroxytryptamine receptor 7 (HTR7) governs the cAMP and G-protein signaling pathways. This altered metabolic homeostasis engenders robust resistance in tumor cells against antimetabolite drugs, such as 5-fluorouracil and gemcitabine [ 80 ]. Capitalizing on this distinct metabolic phenotype of HTR7, Saednia et al. [ 81 ] successfully developed a high-affinity radiolabeled probe (99mTc-MPHH) that achieved precise imaging of active metabolism in glioblastoma. Targeting or monitoring HTR7 not only provides a therapeutic entry point to overcome metabolic drug resistance but also establishes a critical benchmark for in vivo visualization of neuro-metabolic traits.

Notably, spontaneous mutations in receptor genes can enable tumor cells to completely uncouple from their dependence on the external metabolic microenvironment. The E306K mutation in the 5-HT2C receptor disrupts the ionic lock structure in the transmembrane domain, inducing a state of sustained activation that is independent of 5-HT ligand binding [ 82 ]. This constitutive activation mechanism represents an advanced metabolic evasion strategy, permitting tumors to persistently advance their pathological metabolic networks, even in severely depleted environments lacking neurotransmitter supply.

Clinical interventions targeting the 5-HT axis should not be restricted to reducing environmental neurotransmitter concentrations. Instead, specific receptor antagonists (e.g., HTR2B or HTR7 blockers) must be employed to fundamentally sever the signaling networks that drive tumor anabolism and chemoresistance at their source ( Fig. 3 ).

Dopamine

DA exhibits highly receptor-dependent and dual regulatory properties in tumor metabolism. It can drive hypoxic adaptation and anabolism via specific receptors; however, under precise targeted intervention, it can also precipitate mitochondrial collapse in tumor cells and trigger immunometabolic resuscitation within the microenvironment [ 83 ].

The pro- and antitumorigenic effects of dopamine do not occur randomly; rather, they are strictly dictated by the activated receptor subtypes and the differential responses of downstream mitochondrial bioenergetics. Regarding pro-tumorigenic mechanisms, dopamine released during psychological stress activates the D2 receptor (DRD2), which directly upregulates HIF-1α [ 84 ]. This stress-DRD2-HIF-1α axis drastically enhances the metabolic survivability of tumor cells in hypoxic microenvironments, with DRD2 acting as a driver of metabolic reprogramming in tumor cells. Conversely, activating the D1 receptor (DRD1) triggers calpain-dependent endoplasmic reticulum stress, inflicting irreversible damage upon mitochondria and completely arresting glioblastoma proliferation [ 85 ]. Furthermore, specific antagonism of DRD2 using agents such as ONC201 not only disrupts the intrinsic mitochondrial function of cancer cells but also induces profound metabolic and inflammatory reprogramming of tumor-associated macrophages (TAMs) within the microenvironment [ 86 ]. This reverses their phenotype from pro-tumorigenic to anti-tumorigenic and inflammatory. The mechanism underlying this functional divergence is that DRD2 generally functions as a survival driver, maintaining tumor hypoxic metabolism and microenvironmental immunosuppression. In contrast, DRD1 activation or pharmacological DRD2 blockade acts as a mitochondrial toxin capable of thoroughly dismantling the energetic hub of malignant proliferation ( Fig. 3 ).

However, the efficacy of metabolic therapies targeting dopamine receptors is limited by the complex epigenetic and transcriptional remodeling mechanisms of tumors. In solid tumors, such as pituitary neuroendocrine tumors, dopamine receptor expression is frequently silenced. Promoting histone acetylation using valproic acid or utilizing the transcriptional coactivator p300 can robustly restore DRD2 transcription levels. This epigenetic priming drastically heightens tumor sensitivity to dopamine agonists (e.g., bromocriptine), subsequently shutting down mTOR-driven anabolism by suppressing the mTOR-Pttg1 axis [ 87 , 88 ]. During this process, phosphorylated Filamin A serves as a critical biomarker for evaluating the potential of dopamine therapy in reversing metabolic resistance [ 89 ]. Therefore, the combinatorial use of epigenetic modifiers and receptor-targeted agents can effectively reconstruct dopamine-driven metabolic networks [ 90 ].

Given the double-edged nature of dopamine signaling in hypoxic adaptation and mitochondrial toxicity, future precision therapies must abandon non-selective dopaminergic interventions. Coupling epigenetic sensitization strategies with the directed antagonism of DRD2, aimed at inducing tumor mitochondrial collapse and anti-cancer resuscitation of macrophages, represents a critical pathway for treating highly aggressive central nervous system and neuroendocrine tumors.

Regulation of neuroendocrine hormones on the metabolic homeostasis of TME

Glucocorticoids and thyroid hormones

Glucocorticoids (GCs), endogenous stress hormones with potent anti-inflammatory properties, are heavily integrated into cancer therapy [ [91] , [92] , [93] ]. However, circulating levels of adrenal hormones and GCs metabolites strongly correlate with the incidence of cancer, implicating them in oncogenesis [ 94 , 95 ]. Most solid tumors predominantly activate one or more GCs fuel signal transduction systems to exert their effects on the tumor. In tongue squamous cell carcinoma (TSCC), the combination of GCs and the Src kinase inhibitor Dasatinib, is synergystic and exhibits anti-cancer effects by mesenchymal-epithelial transition factor (MET) kinase downregulation [ 96 ]. In contrast, in prostate cancer, the ability of tumor cells to use GCs as a substitute driver is one of the biggest obstacles in the development of therapy-induced tumor resistance. This demonstrates that controlling the metabolism of glucocorticoids is a necessary strategy to prevent tumors from responding to treatment [ 97 ] ( Fig. 4 ).

Triiodothyronine (T3), the terminal effector of the hypothalamic-pituitary-thyroid axis, profoundly dictates TME remodeling [ 98 , 99 ]. Its metabolic influence is highly tissue-specific, acting either as an oncogenic driver or a tumor-suppressive homeostasis regulator ( Fig. 4 ). In breast cancer, T3 accelerates proliferation by modulating intracellular Ca 2+ fluxes, a critical second messenger dictating mitochondrial bioenergetics and cell cycle progression [ 100 ]. In prostate cancer, T3 is a positive regulator of the endoplasmic reticulum-associated degradation (ERAD) pathway, ensuring that AR signaling is active. This reprograms the metabolism of protein synthesis and degradation, which in turn supports the energetic requirements for the growth of androgen-dependent tumors [ 101 ]. In contrast, T3 shows tumor-suppressive properties in HCC by eliminating the phosphorylation of ERK kinases, further contributing to the inhibition of malignancy [ 102 ]. Context-dependent regulation is further evidenced during Nrf2-driven proliferation of hepatocytes, where T3 preserves hepatic homeostasis and halts tumorigenesis by restraining aberrant ERK metabolic signaling [ 103 ].

These findings highlight the value of personalized medicine approaches in practice. For instance, the use of DNA methylation profiling as a high-throughput technique for the precise identification of patients likely to benefit from GCs is a promising avenue. For instance, the DNA methylation atlas established in glioma serves as a pharmacodynamic biomarker for GC sensitivity, thereby predicting survival outcomes following GC therapy. It is a useful tool that integrates the molecular and clinical frameworks of targeted metabolic control [ 104 ]. Concerning thyroid hormones, the distinct metabolic roles of T3, which are localized at the tissue level and from metabolic stabilization to Ca 2+ homeostasis, imply that future translational studies should consider a shift toward approaches centered on metabolism. This is exemplified by the development of tissue-selective TRβ agonists that aim to induce metabolic control through liver-directed tumor-suppressive effects.

Melatonin

Melatonin is a hormone primarily produced by the pineal gland and is widely known for its role in regulating circadian cycles [ 105 ]. Its role in cancer is more complex and involves the regulation of the underlying metabolism ( Fig. 4 ). Melatonin is unique in its redox (reduction–oxidation) capacity, as it protects normal cells from oxidation but can be cytotoxic to cancerous cells via ROS production [ 106 ]. Consequently, melatonin-mediated tumor suppression operates through a tripartite mechanism involving bioenergetic blockade at the metabolic source, organelle-specific intervention, and metabolic sensitization in combinatorial therapies.

In melanomas, melatonin orchestrates a profound metabolic shift characterized by the uncoupling of oxidative phosphorylation, suppression of glycolysis, and dissipation of the mitochondrial transmembrane potential. This metabolic inhibition drastically curtails glucose uptake and triggers a surge in ROS generation, effectively disrupting the energy supply at the source of the tumor [ 107 ]. This glycolytic suppression was corroborated in breast cancer cells by Lai et al. [ 108 ], who demonstrated that melatonin targets the YAP1-NAMPT signaling axis. This action not only inhibits glycolysis but also disrupts DNA repair mechanisms, thereby blocking metabolic adaptation. This tumor-suppressive attribute in breast cancer is intrinsically linked to melatonin-mediated regulation of circadian rhythms and immunometabolism, highlighting its systemic metabolic impact [ 109 ]. Beyond direct intracellular targeting, melatonin effectively ameliorates hypoxic TMEs. By downregulating the activity of hypoxia-inducible factors, it suppresses angiogenesis, metastasis, and metabolic reprogramming in lung cancer [ 110 ]. The regulatory effects of melatonin extend to lipid metabolism through epigenetic mechanisms. In prostate cancer, melatonin induces epigenetic modifications in the CES1 promoter region, thereby restoring its expression. This restoration inhibits aberrant intracellular lipid accumulation, thereby impeding disease progression [ 111 ].

As a cellular powerhouse, melatonin has the capacity for precise targeted intervention. In castration-resistant prostate cancer, conjugating melatonin with a triphenylphosphonium cation to create "Mito-Mel" achieved a remarkable >1000-fold enhancement in anticancer potency. This modification specifically directs molecules to mitochondrial metabolic pathways, offering a novel strategy to overcome metabolic adaptation following androgen deprivation therapy [ 112 ]. Metabolic stress at the organelle level also encompasses the endoplasmic reticulum (ER). Melatonin activates the unfolded protein response via the PERK-ATF4 pathway, initiating apoptosis and suppressing choriocarcinoma development [ 113 ]. The dual role of melatonin in redox metabolism, that is, cytoprotection for healthy cells versus apoptosis induction for cancer cells, offers distinct advantages in combination therapies. When combined with the metabolic drug metformin, melatonin effectively mitigates lysosome-induced autophagy and oxidative stress, highlighting its flexibility in metabolic interventions [ 114 ]. Liu et al. [ 115 ] further revealed that in prostate cancer, melatonin suppresses apurinic/apyrimidinic endonuclease. This inhibition of DNA repair pathways acts synergistically with metabolic stress to significantly arrest tumor growth. Additionally, in non-small cell lung cancer, co-treatment with melatonin and oTR triggers systemic shifts in both metabolomic and transcriptomic profiles, resulting in synergistic anticancer effects [ 116 ].

Collectively, these multidimensional metabolic features position melatonin as a potent natural immunomodulator and antioxidant. By inducing mitochondrial disruption, executing epigenetic modifications, and modulating enzymatic activity, melatonin destabilizes metabolic homeostasis in malignant cells [ 117 ]. These findings provide a robust theoretical foundation for using melatonin as a broad-spectrum, metabolic-regulatory anti-cancer agent to improve the prognosis of conventional cancer therapy.

Reverse regulation of the nervous system by tumor-derived metabolites

Bidirectional regulatory mechanisms governing the interplay between metabolites and neuronal activity within the TME have emerged as pivotal in cancer neuroscience. Current studies have established a clear bidirectional relationship between neuronal function and tumor-released metabolites. Tumor-derived metabolites are no longer viewed merely as energetic byproducts of cell proliferation; instead, they act as crucial signaling molecules that directly or indirectly orchestrate profound remodeling of both the central and peripheral nervous systems (CNS and PNS) [ 118 ]. This metabolic crosstalk not only facilitates tumor progression and immune evasion but also serves as the core mechanism underlying cancer-associated neurological symptoms, including epilepsy, cognitive impairment, cancer pain, depression, and cachexia [ 119 , 120 ] ( Fig. 5 ).

Glycolipid metabolites

Lactate

Lactate, enriched by glycolysis in solid tumors, has transcended its traditional classification as a metabolic waste product. It has emerged as a core metabolic substrate and epigenetic signaling molecule, playing a dominant role in disrupting neuro-glial metabolic homeostasis, inducing aberrant neurogenesis, and driving perineural invasion (PNI). The utilization of lactate within the TME exhibits highly networked transcellular characteristics. Ruan et al. [ 121 ] demonstrated that breast cancer stromal cells secrete extracellular vesicles containing miR-199b-5p, which target and downregulate the solute carrier family 16 member 7 (SLC16A7) transporter on the surfaces of neurons and astrocytes. This metabolic hijacking forcibly blocks physiological lactate clearance in the nervous system, leading to substantial accumulation of extracellular nutrients that are subsequently scavenged by cancer cells to fuel their invasive growth. In contrast, lactate directly acts as a signaling molecule to alter neuronal functional states. Xu et al. [ 122 ] revealed that upon monocarboxylate transporter 1 (MCT1)-mediated intracellular transport, lactate specifically protects the N-Myc downstream regulated gene 3 (NDRG3) protein from degradation, enabling its stable intracellular accumulation. Subsequently, stabilized NDRG3 activates the TEAD1/ELF4 transcriptional complex, upregulating neurogenesis-related genes, such as SPARC-like 1. This cascade induces significant neuronal-like differentiation and massive axonal outgrowth in neuroblastoma.

Deconstructing the neural-tumor metabolic crosstalk network provides a robust translational foundation for the non-invasive diagnosis of neurologically associated tumors and the development of next-generation precision medicine. At the diagnostic level, leveraging hyperpolarized magnetic resonance imaging (MRI) technology to dynamically monitor the enzymatic conversion of [13C] pyruvate to lactate has enabled clinicians to capture unique redox imbalances within tumors with high sensitivity [ 123 ]. This noninvasive metabolic imaging technique provides a visually quantifiable molecular-level indicator for evaluating the metabolic heterogeneity and invasive potential of nervous system tumors. Therapeutically, optimal prognostic regimens will inevitably evolve toward combinatorial intervention models. As research advances, it is evident that isolated metabolic blockade is insufficient to overcome complex microenvironmental compensation. The deep integration of metabolic pathway interventions (e.g., targeting MCT transporters or nucleotide metabolic enzymes) with targeted neuromodulation (e.g., inhibiting specific neurotransmitter receptors or ion channels) is bound to open a novel therapeutic avenue in precision oncology, capable of thoroughly dismantling the tumor-nerve symbiotic network.

Lipids

Lipid metabolic reprogramming within the TME, along with the concomitant secretion of bioactive lipid metabolites, fundamentally rewires the neuro-immune networks of the CNS.

In primary CNS malignancies, these locally secreted metabolites function as potent signaling mediators that critically accelerate tumor deterioration and cachexia production. Within the glioblastoma (GBM) niche, interleukin-1β (IL-1β)-producing TAMs markedly amplify the prostaglandin E2 (PGE2)-EP4 signaling axis. As a highly reactive derivative of arachidonic acid, PGE2 directly orchestrates profound localized immunosuppression and drives unchecked cellular proliferation, thereby fueling the malignant trajectory of GBM [ 124 ]. In addition to primary lesions, systemic lipid dyshomeostasis and aberrant expression of lipid-metabolizing enzymes serve as core catalysts for neural invasion in peripheral cancers. In acute myeloid leukemia (AML), systemic hypercholesterolemia coupled with dysregulated expression of CES1, a pivotal lipid metabolic gene, directly perturbs the immune infiltration landscape within the CNS. This microenvironmental reconfiguration, driven by disrupted cholesterol handling and lipid genetics, is critical for precipitating CNS relapse in AML [ 125 ].

Consequently, precision targeting of specific lipid metabolic nodes, such as the pharmacological blockade of PGE2 signaling or the restoration of cholesterol homeostasis, emerges as a compelling therapeutic strategy to halt the progression of neuro-oncological diseases and preempt CNS metastasis and relapse.

Mutated metabolite of IDH

IDH mutations drive the massive synthesis and extracellular release of the oncometabolite D-2-hydroxyglutarate (D-2-HG). This metabolite directly remodels neuronal networks within the microenvironment, serving as the principal instigator of pronounced central neuronal excitotoxicity and epileptogenesis. Locally secreted by IDH-mutant gliomas, D-2-HG induces the aberrant remodeling of adjacent neuronal synaptic architecture in a mechanism dependent on the hyperactivation of the mTOR (mammalian target of rapamycin) pathway, this process augments the TCA cycle, thereby potently fueling microenvironmental epileptogenesis [ 126 ]. Consequently, due to the intractable local accumulation of this metabolite, patients with IDH-mutant tumors are frequently afflicted with highly challenging pharmacoresistant seizures [ 127 ]. Thus, D-2-HG transcends its role as a mere signature biochemical byproduct of IDH-mutant tumors and acts as a critical pathogenic neurochemical signaling molecule that directly alters local synaptic excitability, precipitating aberrant neuronal discharges and seizure activity.

Specific inhibitors targeting the mutant IDH enzyme and its aberrant metabolic cascade are not merely efficacious in arresting glioma growth; they represent a transformative therapeutic modality for abrogating neuronal excitotoxicity at its source and controlling pharmacoresistant seizures. With the expanding clinical integration of IDH-targeted agents (e.g., ivosidenib) [ 128 , 129 ], their efficacy in ameliorating neurological symptoms has been firmly validated [ 130 ]. Clinical evidence further demonstrates that the administration of IDH1 inhibitors significantly attenuates the risk of postoperative seizure recurrence [ 131 ]. Remarkably, these agents have yielded profound reductions in seizure burden among patients with IDH1-mutant oligodendrogliomas suffering from drug-resistant epilepsy [ 132 ]. Collectively, the targeted blockade of IDH oncometabolite production successfully severs the vicious cycle of "metabolite release–neuroexcitotoxicity." This underscores the centrality of targeted metabolic interventions in achieving the dual clinical endpoint of halting tumor progression and mitigation.

Nucleotide metabolites

Within the highly heterogeneous TME, massively synthesized, secreted, or depleted purinergic metabolites can directly infiltrate or perturb the nervous system of the host. These metabolites disrupt neuroimmune crosstalk, energetic homeostasis, and neurotransmission, thereby precipitating intractable clinical syndromes, such as cancer-related fatigue, depression, cognitive decline, and cachexia.

The pathological buildup of adenosine within the TME triggers widespread neuroinflammation by hyperactivating specific receptors, most notably the A2A receptor (A2AR) in the CNS. This cascade directly drives accelerated brain aging and severe cognitive impairment in patients with cancer. Adenosine and its cognate receptor network (A1, A2A, A2B, and A3) function as central signaling hubs governing both neuropathological and oncological progressions, with their molecular pharmacology extensively validated [ [133] , [134] , [135] , [136] , [137] ]. High concentrations of adenosine act as primary mediators propelling both local and systemic inflammation [ 138 ]. Among cancer survivors, aberrantly hyperactive A2AR signaling directly dictates accelerated neural senescence, constituting the core pathological mechanism underlying cancer-related cognitive impairment [ 139 ]. Therefore, high concentrations of tumor-derived adenosine are not inert metabolic waste; rather, they serve as critical pathogenic agents that provoke CNS toxicity and long-term cognitive deterioration via receptor-dependent neuroinflammatory cascades.

In addition to exerting direct neurotoxicity, tumor-derived adenosine dynamically modulates the permeability of the blood-tumor barrier (BTB) within the CNS to promote malignant phenotypes. Specifically, targeted activation of A2AR significantly increases BTB permeability in murine glioma models [ 140 ]. Consequently, the pharmacological community is vigorously developing highly selective A2AR antagonists, ranging from classical caffeine analogs to novel non-xanthine and quinazoline derivatives, to confer robust neuroprotection while simultaneously thwarting tumor immune evasion [ [141] , [142] , [143] , [144] ]. Furthermore, specific adenosine derivatives and methyl donors originating from peripheral solid tumors can traverse the BBB as long-range endocrine modulators, directly rewiring the electrophysiological activity of the central nervous system (CNS). The perturbation of neural circuits by oncometabolites is not confined to the local TME and exerts profound systemic repercussions. For instance, Yang et al. [ 145 ] revealed that the sustained release of S-adenosylmethionine (SAM) by tumors acts as an endocrine messenger, effectively permeating the BBB. Upon entering local neurons, SAM is incorporated as a substrate by RNA methyltransferase methyltransferase like 14 (METTL14), propelling epigenetic remodeling. This pathological transcriptional reprogramming directly provokes persistent hyperexcitability in the regional neurons. High SAM concentrations drive aberrantly elevated neuronal firing rates and sustained excitotoxicity, providing a precise biological mechanistic rationale for the high clinical incidence of comorbid refractory cancer pain and depression among oncology patients. These findings substantiate that energetic and methylating metabolites, including lactate, ketone bodies, and SAM, possess dual "metabolic substrate-neuromodulator" properties. By altering the electrophysiological thresholds and synaptic plasticity of central neurons, these molecules systematically expand the pathological boundaries of the TME across the neuraxis [ 146 ]. Targeted blockade of the trans-barrier transport of these pathogenic metabolites to rectify the ensuing electrical dysregulation represents a novel translational paradigm for intercepting CNS comorbidities and enhancing the quality of life in patients with advanced-stage disease.

To sustain high-intensity glycolysis, tumor cells ruthlessly exhaust purine-containing coenzymes (such as NAD + ) in the local microenvironment. This plundering of critical energetic signaling molecules accelerates metabolic senescence and cognitive decline in adjacent normal neural tissues. Nicotinamide adenine dinucleotide (NAD + ), an essential coenzyme harboring an adenine (purine derivative) moiety, executes indispensable functions in orchestrating cellular energy metabolism, DNA repair, and signal transduction [ 147 ]. However, the hyperglycolytic phenotype of tumors severely depletes local NAD + pools. This metabolic disequilibrium directly impedes key NAD + -dependent anti-aging longevity proteins, such as SIRT6, from exerting their canonical neuroprotective functions [ 148 ]. This tumor-instigated localized NAD + starvation forces normal neurons into a severe energetic crisis, accelerating cellular senescence.

Collectively, targeting the adenosine signaling axis and its receptor network, or modulating the reservoirs of critical purinergic energetic metabolites such as NAD + within the TME, pioneers a novel frontier in precision translational medicine for reversing cancer-associated neurological comorbidities, including cognitive impairment and neuroinflammation.

Tryptophan metabolites

Malignant tumors drive a massive accretion of neurotoxic metabolites both locally and systemically through hyperactivation of the kynurenine pathway (KP). This pathological buildup not only fuels tumor progression but also directly insults central neurons, precipitating cancer-related cognitive decline and severe neurotoxic syndromes in patients with cancer. Evidence indicates that malignancies, such as glioblastoma, exhibit a profound reliance on tryptophan metabolism to sustain their tumorigenicity and orchestrate both immune evasion and therapeutic resistance [ 149 ]. As tryptophan is massively shunted into the KP, the downstream metabolites generated, such as quinolinic acid, manifest potent neurotoxicity. Consequently, tumor-driven KP hyperactivation extends far beyond localized metabolic rewiring, and the ensuing flood of neurotoxic metabolites serves as the direct biochemical culprit underlying acute and chronic encephalopathies, memory deficits, and treatment-induced neurotoxicity in patients with cancer [ 150 ].

The concentration gradients of tryptophan metabolites within the TME are strictly dictated by local rate-limiting enzymes. These metabolites directly propel glial inflammatory responses, whereas targeting these requisite enzymes can effectively dismantle the inflammatory niche, thereby exerting robust neuroprotective and analgesic effects. In neoplastic brain tissues, such as human astrocytomas, kynurenine 3-monooxygenase (KMO), the primary rate-limiting enzyme responsible for catalyzing kynurenine downstream, undergoes pronounced pathological alterations in both expression and enzymatic activity [ 151 ]. Aberrant tryptophan metabolism driven by KMO and allied enzymes serves as the central engine igniting localized glial neuroinflammation within the tumor. Pharmacologically rewiring this metabolic axis not only strips the tumor of its immune evasion advantages but also emerges as an intervention strategy with immense translational value for combating cancer-associated neuropathic pain and conferring neuroprotection.

Neurometabolic-driven tumor drug resistance and treatment strategies

In solid tumors, neurotransmitters and hormonal signals often converge to promote chemotherapy resistance by activating glycolysis-centric metabolic axes. In intrahepatic cholangiocarcinoma (ICC), He et al. [ 152 ] demonstrated that EPI and NE induce metabolic reprogramming via sustained activation of the ADRB2-glycolysis signaling axis. This activation confers resistance to gemcitabine in tumor cells by upregulating key glycolytic enzymes (HK2), transporters (GLUT1), and multidrug resistance proteins (MDR1/ABCG2), thereby promoting glucose metabolism. Similarly, in cholangiocarcinoma (CCA), T3 exhibits potent metabolic reprogramming. Studies have shown that T3 stabilizes HIF-1α, which subsequently upregulates GLUT1. Activation of the T3-HIF-1α-GLUT1 axis significantly amplifies glycolysis and directly confers gemcitabine resistance, underscoring the critical role of thyroid hormones in the bioenergetic adaptation of CCA [ 153 ]. To counter these mechanisms, targeting upstream signaling or downstream metabolic nodes has proven therapeutically effective. Saikosaponin D administration suppresses ADRB2 signaling, thereby reducing glucose metabolism and suppressing resistance-associated protein expression. This intervention significantly reversed multidrug resistance in ICC, establishing the NE-ADRB2 axis as a pivotal therapeutic target for metabolic reprogramming [ 152 ].

Neuro-metabolic signals also induce resistance through intricate epigenetic modifications and amino acid metabolic networks, a phenomenon particularly observed in hematologic malignancies and HCC. GCs are key drivers of TME remodeling, and tumor cells actively exploit or evade GC signaling via epigenetic and enzymatic alterations to achieve immune evasion and resistance [ 154 ]. The response to GCs is highly variable. In T-cell acute lymphoblastic leukemia, resistance stems from the RNA methylation dynamics. Gong et al. [ 155 ] revealed that the m6A demethylase ALKBH5 removes m6A modifications from ubiquitin-specific peptidase 1 (USP1). These deletions stabilize USP1 expression, which subsequently activates Aurora B kinase, inducing GC resistance. Conversely, in B-cell acute lymphoblastic leukemia (B-ALL), small ubiquitin-like modifier (SUMO) ylation modulates GC sensitivity. Pharmacological targeting of this modification with the SUMO ylation inhibitor TAK-981 significantly increases GC-induced cytotoxicity [ 156 ]. Furthermore, downstream metabolic alterations help to determine GC efficacy. In resistant leukemia cells, reliance on aerobic glycolysis alters membrane permeability and ion concentrations to prevent cellular GCs uptake, a metabolic feature with potential as a cytotoxicity biomarker [ 157 ]. In multiple myeloma, targeting lipid metabolism offers a route to reverse resistance. The ω-3 fatty acid EPA modulates the balance between the chaperone Hsp90 and the glucocorticoid receptor, thereby restoring dexamethasone sensitivity through lipid metabolic reprogramming [ 158 ]. Collectively, these findings suggest that inhibition of GR signaling is insufficient, and future strategies must pivot towards dual metabolic-epigenetic interventions [ 159 ]. In solid tumors such as HCC, Li et al. [ 160 ] confirmed that the miR-199a-5p/GPR89A axis induces sorafenib resistance specifically by reprogramming glutamate metabolism. Similarly, overcoming heterogeneity and resistance in breast cancer may require the integration of natural products with conventional therapies to exploit synergistic effects at nodes specific to glutamate metabolism [ 161 ].

Leveraging endogenous hormones with metabolic regulatory functions represents a novel paradigm for restoring therapeutic sensitivity in CRC. Melatonin, a pleiotropic metabolic modulator, has immense translational potential. In bladder cancer, exogenous pyruvate-mimicked glycolysis induces gemcitabine resistance. Melatonin counteracts this effect by downregulating the rate-limiting enzyme, α-enolase (ENO1). Targeting the ENO1-glycolysis axis resensitizes tumor cells to chemotherapy, thereby identifying ENO1 as a metabolic biomarker [ 162 ]. Furthermore, in combination with photothermal therapy, melatonin effectively ameliorates tumor hypoxia and triggers programmed cell death, highlighting its utility in enhancing the efficacy of physical treatments [ 110 ]. In combinatorial regimens, melatonin acts as a potent sensitizer for targeted agents. Liu et al. [ 163 ] found that melatonin potentiates the cytotoxicity of the tyrosine kinase inhibitor neratinib by promoting endocytosis and lysosomal degradation in HER2 receptors, thereby blocking the growth of HER2-positive breast cancer cells. Whether through a combination of natural products targeting glutamate nodes in breast cancer or the blockade of sympathetic pathways in cholangiocarcinoma, future antitumor strategies must integrate neuro-metabolic blockade strategies with existing chemotherapy, targeted therapy, and physical therapy protocols [ 164 ]. This integrative approach is essential for dismantling the metabolic adaptations that sustain therapeutic resistance ( Table 1 ).

Discussion and perspectives

The neuro-metabolic axis, particularly the integration of the energy metabolism framework within the TME and the modulation of the cellular response to metabolic stress, forms the foundational basis of tumorigenesis, adaptive survival, and therapeutic resistance. Despite its importance, the field of cancer neuro-metabolism is relatively new, and consequently, there are many challenges and unanswered scientific questions. First, neuro-metabolic interactions are characterized by spatiotemporal heterogeneity across tumor types and stages of tumor development. This heterogeneity leads to the ineffectiveness of metabolic intervention strategies in these patients. For example, depending on the tumor type, GABA can act as a metabolic inhibitor in one scenario, while in another, it can serve as a pro-tumorigenic agent. This unpredictability poses a challenge to the clinical application of single-agent therapies. Second, targeting neurotransmitter receptors can cause numerous unintended metabolic consequences. For example, central inhibition of β-adrenergic receptors and/or central modulation of neuropeptides can lead to significant adverse effects on the central nervous system and can result in dysregulation of systemic glucose and lipids, and even worsen cachexia, which is directly opposed to the desired therapeutic effects. Concurrently, the physiological integrity of the CNS is strictly contingent upon the precise maintenance of transmembrane ion gradients, a process predominantly driven by the highly ATP-consuming Na + /K + -ATPase (NKA). The bidirectional coupling between the local neurotransmitter microenvironment and the NKA-generated electrochemical gradient underpins cerebral homeostasis [ 165 ]. For instance, the rapid clearance of glutamate from the synaptic cleft relies heavily on excitatory amino acid transporters (EAATs) expressed on the glial and neuronal membranes. Crucially, the kinetic driving force for these transporters is directly harnessed from the Na + gradient maintained by the NKA. Mechanistically, molecular regulation via NDRG2 significantly enhances interstitial glutamate uptake, thereby conferring neuroprotection against excitotoxic injury induced by extracellular glutamate overload [ 166 ]. Collectively, these findings provide compelling, albeit indirect, evidence that preserving robust ion pump dynamics (e.g., NKA activity) is a strict prerequisite for neurotransmitter clearance systems to perform their neuroprotective functions. In addition, the BBB and other structural obstacles limit the ability of metabolic modulators to effectively reach gliomas and metastatic brain lesions. This problem helps explain the large disparity between the in vitro and in vivo effectiveness of neuro-metabolic interventions. Most current research analyzes only static representations of individual metabolites and cannot track real-time changes in metabolic flux during neural control, creating a critical gap in our understanding of dynamic regulatory systems.

To address these challenges, future studies on cancer neuroscience and metabolism should focus on the following areas. It is critically important to identify particular cases connected to neuro-metabolic control at the single-cell level in various TMEs. Identifying key molecules that mediate neural input and metabolic output, particularly GPCR and mitochondrial enzyme complexes, will streamline efforts to identify precision targets that selectively inhibit tumor energy supply. Third, there is a critical need to develop strategies for the first-time control and targeted modulation of neuro-metabolism. This can be achieved through the engineering of site-specific delivery systems using nanodelivery or prodrug approaches to release metabolic modulators at the tumor site or through the development of allosteric inhibitors that reverse specific neural-induced modifications of metabolic enzymes (e.g., HK2, GLS1). The primary objective of these approaches is to localize the therapeutic effects to the tumor microenvironment, resulting in the disruption of tumor energy acquisition while maintaining the endocrine and systemic metabolic homeostasis of the host. To describe the neuro-metabolic network in its entirety, we must fully integrate multiple technologies, especially in developing a new four-dimensional framework for multi-omics dynamic imaging.

The integration of spatial transcriptomics and spatial metabolomics will allow the characterization of neural distribution and hypermetabolic clones in situ, providing an understanding of the role of neural innervation in creating specific metabolic niches. Furthermore, in vivo real-time metabolic imaging of neural activation is possible with hyperpolarized 13C-MRI, which measures the dynamics of metabolic changes in neural activity when other methods are limited to measuring static metabolic processes. The cross-disciplinary application of these techniques with neural circuit tracing methods to track tumor metabolite-induced (lactate, SAM) retrograde functional remodeling of neurons is critical for analyzing malignant neuro-tumor feedback loops to identify and 'plug' the positive feedback loops.

Systematic, translational analyses of neuro-metabolic interactions will increase our understanding of tumor biology and inform novel approaches to combat difficult-to-treat tumors. Targeting neuro-metabolic interactions will provide the means to eliminate the survival support afforded to tumor cells by the neural system, thus reversing the resistance of tumor cells to chemotherapy, radiotherapy, and immunotherapy. The integration of neuro-metabolic interactions within a therapeutic framework may be the first means of addressing resistance and may be the first to provide a clear path to advance precision oncology.

Declarations

Disclosure statement

The authors declare no potential conflicts of interest was reported by the author(s).

Funding

This work was supported by the National Natural Science Foundation of China (82473069), the Natural Science Foundation of Hebei Province (H2025206897, H2024206222) and Clinical Research and Innovation Team Support Program of Hebei Medical University (2022LCTD-A11).

AI-assisted editing statement

This article has been edited with the assistance of an artificial intelligence tool to enhance clarity and fluency, ensuring that the original meaning and scientific accuracy remain intact.

Data availability statement

Not applicable.

CRediT authorship contribution statement

Zhendong Zhang: Writing – original draft, Visualization, Investigation, Conceptualization. Yunlong Jia: Writing – original draft, Investigation, Conceptualization. Tianxu Liu: Visualization, Investigation. Sheng Wang: Writing – review & editing, Funding acquisition. Lihua Liu: Writing – review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors acknowledge Prof. Huixian Cui (International Cooperation Laboratory of Stem Cell Research, Hebei Medical University) for his assistance. The figures are generated by BioGDP ( https://biogdp.com/ ).

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Associated Data

Data Availability Statement

Not applicable.