Vagus nerveAs the primary component of the parasympathetic nervous system, the vagus nerve (VN) constitutes the fastest and most direct anatomical pathway between the gut and the brain. However, vagal nerve endings typically do not physically contact gut microbiota. Instead, they rely on enteroendocrine cells (EECs) and the enteric nervous system (ENS) as signal sensors to mediate indirect gut-brain communication^[16]. More groundbreaking is the discovery that specific EECs can form functional synaptic structures called neuropods with neurons in the vagal nodose ganglion, utilizing neurotransmitters like glutamate to enable millisecond level rapid signal transmission to the brain^[17]. Notably, tryptophan catabolites produced by gut microbiota can not only activate TRPA1 channels on EECs to trigger rapid vagal firing but also, when produced in excess, directly stimulate vagal afferent fibers and induce persistent anxiety-like behaviors^[18]. Concurrently, the modulatory effects of probiotic strains on the CNS are highly dependent on the anatomical integrity of the VN^[19]. Conversely, colonization by pathogenic bacteria induces abnormal expression of c-Fos protein in vagal afferent brain regions, directly triggering host anxiety like behaviors^[20].

Enteric nervous systemFunctioning as the intrinsic control center of the gastrointestinal tract, the ENS not only regulates gut motility, local blood flow, and epithelial secretion but also serves as a fundamental interface connecting the intestinal microenvironment with the host physiological state. Notably, the structural integrity and functional maturation of the ENS are highly dependent on the early colonization and continuous signaling input from the gut microbiota^[21]. During the critical postnatal developmental window, microbiota activate Toll-like receptor signaling pathways, directly driving the survival and differentiation of enteric neurons as well as the recruitment of glial cells^[22]. Furthermore, microbial metabolites act as signaling molecules to induce enterochromaffin cells to release 5-HT^[23]. This subsequently activates specific receptors on the ENS to precisely maintain gut peristaltic rhythms^[24].

The gut microbiota, functioning as a highly active metabolic hub, continuously generates a series of neuroactive metabolites through the fermentation of dietary fibers and the transformation of endogenous substances. These metabolites thus serve as pivotal messengers in gut-brain communication. Within this intricate metabolic network, SCFAs, primarily acetate, propionate, and butyrate, are core lipid metabolites produced via anaerobic fermentation of dietary fibers^[29]. As these metabolites enter the systemic circulation and reach the CNS, SCFAs demonstrate multifaceted roles. They not only effectively promote neurogenesis and contribute to the establishment of systemic immune barriers but also function as natural HDAC inhibitors^[30]. By means of epigenetic modifications, they significantly ameliorate host cognitive function and alleviate neuroinflammation^[31,32]. Corresponding to the fermentation of carbohydrates, the microbial metabolism of amino acids constitutes another critical axis of the gut-brain pathway. Upon crossing the blood-brain barrier (BBB), these molecules finely tune the activation state of astrocytes by binding to and activating AHR, thereby exerting profound anti-inflammatory and neuroprotective effects^[33]. On the other hand, trimethylamine N-oxide (TMAO), derived from dietary choline metabolism, exhibits a concentration-dependent double-edged sword effect in neuroregulation. Under physiological concentrations, TMAO helps maintain the structural integrity of the BBB, which is crucial for restricting the invasion of peripheral pro-inflammatory factors into the brain^[34,35]. However, when microbial metabolic dysregulation leads to the pathological accumulation of TMAO, it not only induces severe neuroinflammation but also disrupts synaptic plasticity, ultimately resulting in cognitive impairment^[36]. These intertwined metabolic pathways collectively constitute the biochemical foundation through which the gut microenvironment systematically reshapes central nervous function and local immune status.

The ENS, owing to its extensive and highly autonomous neuronal network, is regarded as the most direct interface for the host’s top and down regulation of the gut microbiota. Although ENS neurons do not physically extend into the gut lumen to make direct contact with microbes, they exert profound indirect influences through a sophisticated network of chemical signaling. Specifically, ENS neurons synthesize and release over 30 neurotransmitters, neuropeptides, and neurotrophic factors, including Acetylcholine (Ach), catecholamines, 5-HT, and histamine^[37]. These abundant neural signals not only regulate gut motility, local blood flow, and epithelial secretion but also reshape the local mucosal microenvironment by altering its physicochemical properties^[38]. This, in turn, acts as an environmental selection pressure that indirectly modulates the community composition and metabolic activity of the gut microbiota^[39]. This neuro and microbial regulatory mechanism have been robustly substantiated at the multi-omics level. More importantly, this ENS-based signaling is crucial for maintaining postnatal gut development and microbial homeostasis. Specific genetic knockout or deficiency of choline acetyltransferase in enteric neurons leads to marked motility disorders and inevitably accompanies severe dysbiosis^[40]. This body of evidence strongly suggests that the signaling network of the ENS plays a pivotal hub role in maintaining host and microbe symbiosis.

Within the intricate network of gut-brain communication, the ANS, via the efferent fibers of the sympathetic and parasympathetic nerves, precisely transmits high level commands from the brain to intestinal effector cells. This process systematically reshapes the gut micro ecology at a macroscopic level. Vagal efferent fibers primarily release ACh to act upon EECs, enteric neurons, and other effector cells^[41]. This efferent signaling not only fine tunes gut motility rhythms and glandular secretion but also reflexively screens and restructures the microbial community composition by altering the physicochemical environment within the gut^[42,43]. In parallel with the protective and secretory promoting roles of the vagus nerve, the SNS provides a counter regulatory mechanism for physiological and immune modulation. Sympathetic nerve endings, originating from prevertebral ganglia, primarily release catecholaminergic neurotransmitters such as norepinephrine (NE) into the gut wall^[44]. When sympathetic tone increases, NE binds to adrenergic receptors, directly inhibiting gut motility and mucosal secretion while triggering local microvascular constriction^[45]. This leads to a significant reduction in tissue perfusion. This mediated drastic decline in hemodynamics and gut motility profoundly alters the intraluminal oxygen gradients, pH levels, and nutrient availability^[46]. Acting as a potent environmental selection pressure, it indirectly but strongly determines the survival and colonization advantages of different bacterial taxa^[47]. Therefore, the dynamic interplay between sympathetic and parasympathetic efferent signals within the autonomic nervous system dictates the physical and biochemical characteristics of the gut microenvironment by regulating blood flow and inflammatory responses.

Evidence for AMPAR-mediated electrochemical integration is strongest in high-grade glioma. In these tumors, excitatory neuron-to-glioma synapses (NGS) provide a direct route through which neuronal activity can influence malignant cells^[53]. Glutamate released from presynaptic neuronal terminals binds to Ca²⁺-permeable AMPARs expressed on glioma cells, inducing membrane depolarization and intracellular calcium signaling^[54,55]. These electrophysiological inputs can be propagated among interconnected glioma cells through connexin 43-associated tumor networks, thereby coordinating calcium activity and proliferative responses^[56]. Available evidence is derived predominantly from glioma cell systems, human glioma analyses, and preclinical brain-tumor models. Whether comparable AMPARs-dependent synaptic integration occurs in extracranial solid tumors remains insufficiently established and requires direct electrophysiological and structural validation.

Evidence for NMDAR-mediated neuron-tumor communication is currently most compelling in models of breast cancer brain metastasis. After colonizing the brain, metastatic breast cancer cells can occupy positions adjacent to pre-existing glutamatergic synapses and form pseudo-tripartite arrangements in which tumor-expressed NMDA receptors sense neuron-derived glutamate^[57]. Activation of these receptors promotes calcium influx and downstream signaling that may support metastatic cell survival, adaptation, and outgrowth within the neural microenvironment^[58]. NMDAR-dependent effects on migration or viability have also been observed in selected breast cancer cell systems. However, receptor expression or pharmacological responsiveness alone does not demonstrate the formation of functional neuron-tumor synapses outside the brain. Thus, this mechanism should presently be interpreted as a feature of selected brain-metastatic contexts rather than a general mechanism shared by primary breast tumors or other extracranial solid cancers. In this architecture, NMDAR expressed by cancer cells act as microenvironmental sensors. By receiving glutamate signals released between neurons, they trigger persistent calcium influx and downstream CaMKII signaling cascades. This mechanism not only provides crucial survival signals for tumor cells during the process of metastatic colonization but also enables them to exploit the high concentration of excitatory neurotransmitters in the synaptic cleft as a driving force for growth.

The malignant phenotype of gliomas is largely attributable to their unique anatomical architecture: the tumor microtube (TM) network. Driven by GAP43, these elongated tubular protrusions break the individual boundaries between cancer cells^[59]. Through connexin 43-mediated gap junctions, they couple scattered tumor cells into a functional multicellular syncytium^[60]. Within this architecture, electrical signals from neuronal synapses and glutamate driven calcium influx are no longer confined to local regions^[61]. Instead, they are transformed into population wide synchronous calcium oscillations via the TMs network. This networked mode of survival not only endows tumor cells with the ability for coordinated invasion but also constitutes the structural basis for their extreme resistance to radiotherapy and chemotherapy through collective metabolic support and stress buffering. Tumor microtube-mediated multicellular integration has been characterized most extensively in glioma and should not be equated with connexin expression or intercellular communication observed in other solid tumors. Evidence for structurally and functionally equivalent tumor microtube networks outside the central nervous system remains limited.

Activity-dependent a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10)-NLGN3 signaling has been established primarily in preclinical models of high-grade glioma. Increased neuronal activity promotes ADAM10-dependent ectodomain shedding of membrane-bound neuroligin-3, releasing soluble NLGN3 into the local neural microenvironment^[62]. In susceptible glioma cells, soluble NLGN3 activates growth-associated pathways, including phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) and MAPK signaling, and promotes transcriptional programs that support tumor proliferation and neural integration^[63]. This interaction may generate a positive feedback loop within the glioma microenvironment by increasing the responsiveness of malignant cells to neural activity. However, NLGN3 should currently be regarded as a context-dependent neural niche factor rather than a universally established mitogen for all solid tumors^[64]. Direct evidence for an equivalent activity-dependent ADAM10-NLGN3 circuit in extracranial cancers remains limited.

The role of BDNF-TrkB signaling in activity-dependent neuron-tumor synaptic plasticity has been characterized mainly in glioma models^[65]. Neuron-derived BDNF can activate TrkB expressed by glioma cells and engage downstream PI3K-AKT and MAPK- extracellular regulated protein kinases (ERK) signaling, thereby supporting tumor-cell survival and proliferation^[66]. In addition, BDNF-TrkB signaling can enhance the strength and stability of neuron-glioma synaptic interactions, including through changes in postsynaptic AMPA-receptor abundance, thereby establishing an activity-dependent positive feedback loop^[67]. Although TrkB expression and BDNF-responsive pro-survival signaling have been reported in several malignancies, the specific role of this pathway in strengthening functional neuron-tumor synapses is currently supported predominantly in the neural microenvironment of glioma. Its applicability to extracranial solid tumors therefore requires independent structural, electrophysiological, and functional validation. These central nervous system-specific synaptic mechanisms should be distinguished from neurotrophin-driven nerve recruitment and perineural invasion, which have broader, although still tumor-dependent, evidence in several extracranial malignancies and are discussed below.

In the remodeling of the TME, the nerve growth factor (NGF)- tropomyosin receptor kinase A (TrkA) pathway serves not merely as a bridge for neural regulation but as a positive feedback amplifier driving malignant progression. Tumor cells actively induce the inward ingrowth of surrounding nerve fibers by secreting NGF to establish a chemotactic gradient, thereby achieving structural reconstruction through neurogenesis^[68]. More critically, ingrown neurons and tumor cells form a sophisticated autocrine/paracrine interactive loop via the NGF-TrkA axis. Neuron-derived NGF binds to TrkA receptors on tumor cells, directly driving sustained proliferation and anti-apoptosis through the cascading activation of PI3K/Akt and MAPK/ERK pathways^[69]. Simultaneously, the tumor cells’ own NGF secretion further maintains the growth promoting state of the microenvironment. This neuro-dependent autocrine loop significantly enhances tumor invasiveness and constitutes the core molecular basis of perineural invasion (PNI)^[70]. Therefore, deciphering and blocking this NGF-TrkA feedback axis holds promise as a novel precision therapeutic strategy to inhibit tumor neural invasion and reverse neuro-dependent tumor growth.

As shown in Figure 5, within the TME, the nervous system regulates immune cell function by innervating the tumor matrix through nerve fibers and continuously releasing neurotransmitters and neuropeptides. These neural signals influence the migration, spatial distribution, and functional state of immune cells through a chemokine network. Mediators such as sympathetic neurotransmitters, ACh, and calcitonin gene related peptide (CGRP) not only bind directly to receptors on immune cells but also influence immune cell infiltration and migration by modulating the physical and chemical properties of the TME^[71-73]. The neurotransmitter NE is also known to modulate T cell migration and effector functions in part by binding to β₂ adrenergic receptors^[74]. Acute stress that can act as an immune adjuvant on CD4⁺ T cell mediated immunity, whereas chronic stress contributes to the failure of remote immune surveillance via induced apoptosis in CD8⁺ T cells leading to tumor immune escape^[75]. In addition, chronic stress and sustained β₂ adrenergic signaling upregulate the production level of ACh that can lead to induced tumor associated macrophages (TAMs) reprogramming into M2 type with immunosuppression effect as well as inhibit TNF production in turn enhance their immune suppressed profile^[76,77]. Neuronal signals upregulate immunosuppression and angiogenesis as a consequence of specific receptor scaffolds and downstream pathways, which can favor growth of the neoplasm and spread to distant organs. In addition, nerves control also myeloid derived suppressor cells (MDSCs) and other myeloid populations fueling the tumor immune escape^[78]. Therefore, the nerve and tumor axis constitutes a dynamic system in which neurotransmitters, their corresponding receptors, chemokine networks, and the metabolic state of immune cells collectively determine the immune regulatory landscape of the TME, ultimately influencing tumor progression and treatment response.

Dysregulation of the Wnt/β-catenin signaling pathway serves as a central driver in oncogenesis and cancer progression, acting not only as the core engine for epithelial dedifferentiation and malignant transformation but also as a key molecular hub for cross kingdom communication with the gut microbiota. Fusobacterium nucleatum, utilizes its surface adhesin FadA to specifically bind E-cadherin on colonic epithelial cells^[79]. This interaction induces endocytosis of the receptor, thereby disrupting the homeostasis of β-catenin anchoring at the cell membrane^[80]. Concurrently, the gut microbiota amplifies this signaling cascade by altering the repertoire of local metabolites. Particularly under high fat diet induced bile acid metabolic dysregulation, microbiota derived secondary bile acids act as potent antagonists of the Farnesoid X Receptor (FXR) in the context of compromised genetic stability. Since FXR normally plays a protective role in maintaining intestinal epithelial homeostasis by suppressing β-catenin signaling, this metabolically driven antagonism effectively lifts the negative regulation on the Wnt pathway^[81]. It thereby acts as a critical booster in the transformation of colonic stem cells into cancer stem cells. Moreover, this microbe driven signal dysregulation does not exist in isolation. It is intricately intertwined with inflammatory cues in the microenvironment. Microbiota dysbiosis induced chronic inflammation drives the production of abundant pro-inflammatory cytokines via the toll-like receptor 4 (TLR4)/NF-κB axis, leading to STAT3 pathway activation^[82]. This pathway not only positively synergizes with Wnt/β-catenin signaling, stabilizing its activated state through epigenetic remodeling, but also collaborates with oncogenic bacteria like Fusobacterium nucleatum to create a conducive niche for tumor growth and immune evasion.

In the molecular mechanisms underlying gut microbiota mediated remodeling of the TME, the STAT3 signaling pathway serves not only as a regulatory hub for cell proliferation but also as a critical bridge linking dysbiosis to chronic pro-tumorigenic inflammation. During the pathological progression of colorectal cancer (CRC), sustained activation of STAT3 effectively establishes a permissive condition for tumor growth and immune escape^[86]. Enterotoxigenic Bacteroides fragilis (ETBF) is a prototypical pathobiont driving this pathway. The B. fragilis toxin secreted by ETBF acts as the triggering signal, binding to epithelial cell surface receptors and inducing aberrant phosphorylation of STAT3 through a signaling cascade^[87]. This cascade, initiated by microbial toxins, integrated by STAT3 signaling, and culminating in immune barrier remodeling, constitutes an indispensable logical circuit in the pro-tumorigenic mechanism of the gut microbiota and tumor axis, greatly accelerating the malignant progression of CRC.

As a central sensing mechanism for cytosolic DNA, stimulator of interferon genes (STING) not only serves as a pivotal hub in regulating intrinsic anti-tumor immunity but also enables precision sensitization of immune checkpoint blockade (ICB) therapies through extrinsic microbial intervention. In this context, specific probiotic communities and their metabolites act as potent molecular triggers for pathway activation. Upon local translocation or systemic circulation, these microbial components engage antigen presenting cells and activate the cytosolic sensor cGAS within dendritic cells (DCs), thereby catalyzing the synthesis of cyclic GMP-AMP (cGAMP)^[88]. This subsequently propagates the STING-dependent TBK1-IRF3 signaling cascade, prompting robust synthesis and secretion of Type I Interferons (IFN-I)^[89]. This axis exerts profound efficacy in reshaping the anti-tumor immune landscape. Ultimately, probiotic driven STING activation creates an optimal responsive niche for immune checkpoint inhibitors (ICIs). By synergistically boosting T cell cytotoxicity and tumor specific responses, this mechanism effectively breaches the tumor’s immune escape barriers.

Vagus nerveWithin the complex regulatory network of the gut-neuro-tumor signaling feedback, the VN serves as the fastest and most direct bidirectional communication bridge connecting the gut ecosystem to the CNS, playing a pivotal role in signal transduction. This process typically initiates with the precise sensing of microbial metabolites by gut microbiota. Key chemical signals activating vagal afferent fibers include SCFAs, indole and its derivatives, as well as 5-HT secreted by ECs^[90]. The most canonical pathway among these is the cholinergic anti-inflammatory pathway. Furthermore, the electrical activity of the VN can remotely modulate the function of tumor infiltrating lymphocytes. In CRC models, enhanced parasympathetic activity reduces the expression of immune checkpoint molecules like PD-1 and PD-L1, consequently boosting the anti-tumor efficacy of CD8⁺ T cells^[91]. However, this regulatory effect exhibits marked organ dependency. In gastric cancer, excessive cholinergic signaling may promote the maintenance of cancer stemness and proliferation by activating the Wnt/β-catenin pathway^[92]. This bidirectional loop, initiated by gut microbes, amplified by neural circuits, and ultimately acting upon the tumor immune microenvironment (TIME), not only reveals the precise systemic regulation of local tumors but also provides crucial theoretical support for optimizing cancer therapies through neuromodulation.

After receiving and integrating signals derived from the gut microbiota and their metabolites, the central nervous system can regulate the TME through sympathetic neural outputs. Within this bidirectional communication circuit, the sympathetic nervous system is frequently associated with tumor initiation and progression. Norepinephrine released from sympathetic nerve terminals binds to β-adrenergic receptors expressed on tumor cells, stromal cells, and immune cells^[93]. Activation of β-adrenergic signaling not only promotes cancer cell proliferation, survival, and migration but also induces an angiogenic switch by upregulating vascular endothelial growth factor and matrix metalloproteinases, thereby facilitating neovascularization within the TIME^[94,95]. Furthermore, persistent sympathetic activation induced by chronic psychological stress suppresses the antitumor activity of CD8⁺ T cells and natural killer cells while enhancing the recruitment and immunosuppressive functions of MDSCs, ultimately promoting tumor immune escape^[96].

Parasympathetic nervous systemThe parasympathetic nervous system (PSNS) primarily utilizes ACh as its neurotransmitter, yet its impact on tumorigenesis exhibits profound context dependency and organ specificity. In models of gastric and prostate cancer, the infiltration of cholinergic fibers is often positively correlated with pathological progression^[92]. In these contexts, ACh binds to muscarinic receptors, subsequently triggering the Wnt/β-catenin or epidermal growth factor receptor (EGFR)/ERK signaling pathways, thereby driving the self-renewal of cancer stem cells and cellular infiltration^[97]. However, in breast cancer, PSNS activation demonstrates potential anti-tumor effects^[98]. This protective role may be attributed to its ability to downregulate immune checkpoint molecules like PD-1 and PD-L1 via cholinergic signaling, as well as to induce interferon-gamma (IFN-γ) secretion, consequently enhancing local anti-tumor immune responses^[99].

Direct neural-tumor interactions include structurally distinct processes whose occurrence varies substantially across tumor types and anatomical sites. Functional electrochemical synapses and activity-dependent neural paracrine signaling have been demonstrated most clearly in primary brain tumors and selected brain-metastatic models^[100]. By contrast, direct interactions in extracranial tumors more commonly involve nerve-fiber infiltration, neuropeptide release, neurotrophin signaling, Schwann-cell participation, and perineural invasion^[101]. Therefore, the synaptic mechanisms discussed in the following subsections should be interpreted within the specific context of glioma and brain metastasis rather than as universal features of all solid tumors.

Neurogliomal synapse in glioma and brain metastasisAt the terminal end of the gut-neuro-tumor signaling feedback, tumor cells are not merely passive recipients of remote signals but exhibit a high degree of nicotinamide (NAM). The evidence base differs between tumor types. AMPAR-mediated neuron-tumor synapses and connexin 43-associated multicellular networks are best established in high-grade glioma, whereas NMDAR-dependent pseudo-tripartite interactions have mainly been described in breast cancer brain-metastasis models^[102,103]. They achieve deep physical and biochemical integration by establishing functional synapses with neurons. The core mechanism underlying this integration lies in the ability of malignant cells, particularly high-grade gliomas and breast cancer brain metastases, to express various neurotransmitter receptors, effectively forming NGS^[104]. Metastatic tumors demonstrate a unique synaptic evolutionary strategy, and they form structures known as pseudo tripartite synapses by expressing NMDARs. In this configuration, tumor cells occupy the niche typically held by astrocytes in physiological conditions^[105]. By continuously scavenging glutamate released from neurons, they activate their own NMDAR pathways, thereby gaining a survival advantage and accelerating colonization and expansion within the challenging brain microenvironment^[103]. Notably, the impact of synaptic input is not isolated to single cells. Instead, it is amplified through tumor networks physically coupled by gap junctions, connexin 43. This synchronized calcium wave propagation allows the entire tumor syncytium to respond to neural signals in concert, forming a multicellular integrated network akin to a brain within the brain^[106]. This significantly enhances the tumor’s tolerance to stress injuries. Furthermore, tumors hijack adaptive plasticity mechanisms from the nervous system, such as the BDNF-TrkB pathway, to strengthen synaptic connectivity and quantity, establishing a positive feedback loop that fuels malignant evolution^[67]. These studies establish a mechanistic basis for neural activity-dependent progression in glioma and selected brain metastases. However, comparable functional synaptic integration has not been demonstrated consistently in extracranial primary tumors, and its prognostic or therapeutic relevance should therefore be evaluated separately for each tumor type and anatomical context.

Activity-dependent neural paracrine signaling in gliomaWithin the remote regulation and terminal effects of the gut-neuro-tumor signaling feedback, paracrine factors secreted by neurons constitute a pivotal biochemical signaling network that reshapes the TME. This regulatory mechanism not only provides direct pro-growth stimuli to tumor cells but also induces highly malignant evolutionary traits by mimicking neurodevelopmental pathways. NLGN3 is currently one of the most extensively studied neuroactivity dependent oncometabolites. In the tumor context, neuronal electrical activity induces the upregulation of the protease ADAM10, which precisely cleaves membrane bound NLGN3, facilitating its shedding into secreted neuroligin-3 (sNLGN3) released into the microenvironment^[107]. Once secreted, sNLGN3 binds to receptors on tumor cells, significantly accelerating the proliferation and infiltration of malignancies such as gliomas by potently activating canonical oncogenic pathways including PI3K-mTOR, and ERK^[108]. Of particular importance, this interaction often evolves into a vicious feedback loop. The PI3K pathway activated within tumors can further induce tumor cells themselves to express NLGN3, thereby continuously reinforcing their survival advantage through an autocrine mode^[109]. In glioma, BDNF-TrkB signaling contributes to activity-dependent synaptic plasticity and may strengthen the functional integration of malignant cells with surrounding neural circuits. This synaptic role should be distinguished from the broader prosurvival effects of BDNF-TrkB signaling reported in other cancer-cell systems^[110]. This mechanism essentially represents tumor cells hijacking the brain’s learning and memory plasticity machinery. By strengthening electrophysiological connections with neural circuits, tumors secure sustained nutritional support and immune evasion capabilities. Furthermore, insulin-like growth factor-1 reveals the initiating mechanisms by which external environmental stimuli drive tumorigenesis through neuro paracrine signaling^[111]. Notably, microbial metabolites produced via the gut-brain axis have been shown to modulate central levels of factors like BDNF^[112]. This suggests that distal signals from the gut may indirectly determine the susceptibility and progression rate of central nervous system tumors by regulating the abundance of neural paracrine factors.

The influence of the nervous system on tumor progression transcends direct physical contact or chemical stimulation, extending profoundly into the systemic remodeling and precise modulation of the TIME.

Remodeling of the TIMEWithin the framework of the gut-neuro-tumor signaling feedback, the systemic remodeling of the immunosuppressive environment is not merely a byproduct of neuroactivity, but rather a core mechanism by which the nervous system precisely modulates the TIME. Specifically, the SNS plays a major driving role in this remodeling process. NE released from SNS nerve terminals binds to β₂-adrenergic receptor (β₂-AR) on immune cells^[51]. This interaction activates the cyclic adenosine monophosphate (cAMP)- protein kinase A (PKA) signaling pathway, thereby significantly inducing the recruitment and functional enhancement of MDSCs, as well as driving the polarization of TAMs toward a pro-tumoral M2 phenotype^[113]. Furthermore, neuropeptides secreted by sensory neurons play an indispensable role in shaping this immunosuppressive landscape. This neuro immune interplay is ultimately unified within the macro-context of the gut-brain axis. Gut microbiota and their metabolites, by regulating systemic immune homeostasis, can induce the differentiation of forkhead box P3 (Foxp3+) Tregs, thereby supporting or suppressing local immune remodeling at a systemic level^[114]. Concurrently, upon receiving gut derived signals, the CNS releases glucocorticoids via the hypothalamic-pituitary-adrenal (HPA) axis^[115]. These hormones further synergize with sympathetic signals to suppress both innate and adaptive immune responses^[116]. Therefore, the neural remodeling of the immunosuppressive milieu is a multi-tiered process. It weaves together the biochemical signals from gut microbiota, the electrophysiological signals from peripheral nerves, and the reconstructed local immune boundaries.

Parasympathetic/vagal immune regulationWithin the regulatory framework of the gut-neuro-tumor signaling feedback, the parasympathetic nervous system plays a pivotal inhibitory role in maintaining immune homeostasis within the TME via neuro-immune reflex circuits. ACh, the primary neurotransmitter released by vagal efferent fibers, binds to alpha-subunit of acetylcholine receptor (α-AChR) on the surface of myeloid immune cells^[117]. This interaction activates the cholinergic anti-inflammatory pathway, significantly suppressing the production and release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), IL-1β, interleukin-6 (IL-6), and IL-18^[118]. This top and down immunomodulatory mechanism not only alleviates the chronic inflammatory milieu that drives tumor progression but also reshapes the immune cell landscape within the TME. In pancreatic cancer, cholinergic signaling exhibits significant anti-tumor activity by reducing the pro-tumoral polarization of TAMs and diminishing cancer stem cell phenotypes^[119]. However, the contribution of vagal signaling to host immune defense is most intuitively demonstrated in ablation studies. In pancreatic ductal adenocarcinoma (PDAC) models, surgical vagotomy leads directly to increase CD8⁺ T cell infiltration, an imbalance in helper T cell ratios, and aberrant activation of macrophage-mediated inflammatory signaling pathways^[120,121]. This systemic impairment of immune surveillance not only lifts the suppression on tumor growth but also accelerates early lesion onset and migration, ultimately significantly shortening survival. This negative feedback mechanism within the neuro-immune-tumor axis reveals that metabolites produced by gut microbiota may trigger central responses via vagal afferent fibers, which then achieve remote fine-tuning of the local tumor immune landscape via vagal efferent fibers and cholinergic pathways. It is worth noting that this immunomodulatory role of the vagus nerve is highly tissue-specific. Although it manifests as an anti-tumor effect in pancreatic cancer, cholinergic signaling may conversely promote tumor cell proliferation by activating the M3R/Wnt signaling pathway in gastric cancer^[122].

Within the gut-neuro-tumor signaling feedback, tumors are not merely passive recipients of microbial and neural signals. Instead, they actively reshape this cross-system network through two complementary mechanisms. Locally, tumors promote neoneurogenesis and PNI by recruiting and remodeling peripheral nerves. Systemically, tumors disturb brain activity, activate the HPA axis, and impair intestinal and microbial homeostasis. Together, these local and systemic feedback routes reinforce tumor progression, immune dysregulation, and therapeutic resistance.

Neoneurogenesis and perineural invasionWithin the dynamic interplay of the gut-neuro-tumor signaling feedback, tumors are not merely passive recipients of signals. Instead, they actively reshape the local microenvironment and accelerate their malignant progression by inducing neoneurogenesis and PNI. This process often begins with the tumor’s targeted recruitment of the nervous system. Through paracrine signaling, tumor cells secrete a variety of neurotrophic factors, including NGF, BDNF, and glial cell line-derived neurotrophic factor (GDNF)^[123]. Analogous to angiogenic factors, these molecules induce the sprouting of new axons into the tumor mass, resulting in a significant increase in intratumoral nerve fiber density, often several fold higher than in non-tumorous tissues^[124]. This active recruitment of nerve fibers provides tumor cells with a unique migratory pathway. During PNI, malignant cells migrate and spread along the nerve sheaths, frequently exhibiting neural tracking behavior^[125]. Notably, this process can occur even prior to lymphatic or vascular involvement. Such invasion relies not only on physical contact but also involves the formation of a specialized perineural niche. Within this unique biochemical microenvironment, invading tumor cells disrupt the perineurium, triggering a cascade of inflammatory cytokines that further promote both neural remodeling and tumor cell survival^[126,127]. Collectively, neoneurogenesis and perineural invasion establish a local positive feedback loop in which tumors recruit and remodel neural structures, while the resulting neural inputs further support tumor survival, invasion, and immune evasion. Beyond this local neural remodeling, tumors can also perturb central neuroendocrine regulation and intestinal homeostasis, as discussed in the following subsection.

Tumor-induced disruptionTumors do not merely respond to neural signals but can actively disrupt central nervous system function and its homeostatic communication with the gut. At the local level, glioma cells release excessive amounts of excitatory neurotransmitters, particularly glutamate, resulting in markedly elevated extracellular glutamate concentrations in the peritumoral region and increased excitability of surrounding neurons^[128]. This neuronal hyperexcitability constitutes an important mechanism underlying tumor-associated epilepsy. At the systemic level, cancer and cancer-associated psychological or physiological stress can chronically activate the hypothalamic-pituitary-adrenal axis, increasing the release of glucocorticoids and catecholamines^[129,130]. Persistent HPA-axis activation subsequently alters gastrointestinal motility, mucosal secretion, immune regulation, and epithelial barrier integrity through descending neuroendocrine and autonomic pathways^[131]. These changes can disrupt gut microbial homeostasis, typically reducing the abundance of short-chain fatty acid-producing bacteria while favoring the expansion of potentially pathogenic taxa^[132]. Barrier impairment may further facilitate the entry of microbial products and inflammatory mediators into the systemic circulation. These circulating signals can aggravate neuroinflammation and reshape the tumor immune microenvironment, thereby feeding back to support tumor progression and immune escape^[133]. Consequently, a tumor-initiated process can be amplified through central neuroendocrine signaling and gut dyshomeostasis before returning to the TME. This forms a self-reinforcing systemic feedback loop that extends the biological effects of a localized tumor beyond its primary anatomical site.

The gut-tumor microbiota axis constitutes the cutting edge of research into the TME, revealing profound spatial coupling and functional synergy between the intestinal ecosystem and spatially segregated neoplastic tissues. At the core of this axis lies the mechanism by which gut microbiota, serving as a primary reservoir, undergo translocation and establish colonization within tumor sites through diverse biological pathways.

Intratumoral bacteriaIn Table 3, within the dynamic interplay of the gut-neuro-tumor signaling feedback, microbial translocation is not merely the material basis for biochemical signal transduction but also the spatial prerequisite for the evolution of gut commensals into intratumoral microbiota. The gut, serving as the body’s largest microbial reservoir, allows its microbiota to cross anatomical boundaries under pathological conditions. These microbes migrate to distal tumor sites via barrier injury, systemic circulation, and anatomical retrograde pathways^[134]. This spatial relocation of microbes ultimately establishes a distinct colonization pattern within the tumor locale. The TME, characterized by hypoxia, nutrient enrichment, and immunosuppression, provides an ideal niche for these translocated microbes^[135]. They are able to persist in an intracellular manner, residing within the cytoplasm of either tumor cells or immune cells. These colonized intratumoral bacteria are not passive bystanders. By producing metabolites, inducing host DNA damage, and activating oncogenic pathways, they actively participate in shaping the TME^[136].

Direct mechanismsSome microbial products directly induce genomic instability or activate oncogenic signaling, whereas others modulate antitumor immunity, epithelial barrier integrity, or treatment responsiveness^[137]. Beyond such direct genotoxic injury, microbes drive the evolution of the malignant phenotype by precisely hijacking the host’s pre-existing signaling networks^[138]. In this regard, the aberrant activation of the Wnt/β-catenin pathway is considered a key pathological mechanism^[139]. This multidimensional mechanism, ranging from physical damage to the systematic subversion of oncogenic signaling, transforms microbes from mere biological bystanders into co-drivers of tumor initiation and progression. As summarized in Table 4, microbiota-derived metabolites, structural components, virulence factors, and other bioactive products can exert either tumor-promoting or tumor-suppressive effects. These effects are highly dependent on the chemical identity of the microbial product, its concentration, the host and tumor context, and the experimental model. They thus constitute a critical cornerstone of biochemical communication within the gut-neuro-tumor signaling feedback.