Neural regulation of cancer: from synaptic integration to neuro-immune regulation

Abstract

The emerging field of cancer neuroscience has reshaped our understanding of tumor biology, showing that the nervous system is an active participant in the tumor microenvironment. It modulates tumor progression through synaptic communication with cancer cells, paracrine signaling via neurotransmitters and neuropeptides, and indirect regulation of the tumor immune microenvironment. Recent discoveries have shown that neurons form synapses with brain tumors and peripheral cancers, driving tumor cell proliferation and invasion. Neurotransmitter and neuropeptide signaling activates pathways in cancer cells to promote malignancy. Furthermore, the nervous system shapes anti-tumor immunity by modulating T cells, natural killer cells, macrophages, and myeloid-derived suppressor cells, creating either an immunostimulatory or, more commonly, an immunosuppressive microenvironment that facilitates immune evasion and treatment resistance. The clinical significance of the neuro-immune-tumor axis is confirmed across multiple cancer types. Consequently, therapeutic strategies targeting neural regulation are emerging, including neurotransmitter receptor blockers, denervation techniques, neuromodulation devices, and approaches to remodel the immune landscape through neural signals. This review synthesizes how nerves regulate tumor progression via synaptic connections, neurotransmitter release, and immune modulation. We also summarize current and emerging therapeutic strategies aimed at disrupting or harnessing neuro-tumor communication. By integrating recent advances, this review aims to establish a framework for understanding neural regulation of cancer and to guide future research and clinical translation in this evolving field.

Introduction

For a long time, the main research of cancer treatment has been focused on fighting against cancer, which aims to eliminate cancer cells as thoroughly as possible through surgery, chemotherapy, and radiotherapy. However, the past decade has witnessed a paradigm shift in our understanding of cancer biology. Tumors are no longer viewed as isolated masses of genetically transformed cells but as intricate organs embedded within the tumor microenvironment (TME) [1]. The tumor microenvironment has long been regarded as a complex system comprising cancer, immune, and stromal cells. However, in recent years, the nervous system has been confirmed as a key player that actively regulates tumor initiation and progression [2–4].

Recent landmark studies have fundamentally challenged the long-held view that neural influences on cancer are indirect or merely epiphenomenal. Breakthrough discoveries have demonstrated that neurons can form bona fide and functional chemical synapses with cancer cells. This phenomenon was first illustrated in glioblastoma, where glutamatergic synapses between neurons and glioma cells drive tumor proliferation and invasion. Remarkably, this direct communication is not unique to brain tumors. Emerging evidence indicates that peripheral cancers, including pancreatic ductal adenocarcinoma and breast cancer brain metastases, can also establish synapse-like connections with sensory and glutamatergic neurons, respectively, thereby co-opting neural activity for malignant progression.

Beyond direct synaptic transmission, neurons extensively modulate tumor behavior through paracrine signaling. Neurotransmitters and neuropeptides—such as norepinephrine, acetylcholine, substance P, and CGRP—are released within the TME where they bind to corresponding receptors on cancer cells. This signaling network directly influences key hallmarks of cancer, including proliferation, survival, migration, and metabolic reprogramming. Simultaneously, perhaps the most profound impact of the nervous system on cancer is exerted through its regulation of the immune system. Neural pathways, particularly the sympathetic and sensory nervous systems, systematically shape the tumor immune landscape by altering the function of T cells, natural killer cells, tumor-associated macrophages, and myeloid-derived suppressor cells, either suppressing anti-tumor immunity or promoting an immunosuppressive milieu that facilitates immune evasion and resistance to immunotherapies.

These insights have opened exciting new therapeutic avenues. Early-stage clinical and preclinical studies are now exploring strategies to disrupt neural-cancer crosstalk, including the use of neurotransmitter receptor antagonists (e.g., β-blockers, CGRP inhibitors), oncolytic viruses targeting intratumoral nerves, and denervation techniques. Furthermore, modulating neural signals to reactivate anti-tumor immunity, often termed “neural checkpoint modulation”, holds promise for enhancing the efficacy of existing immune checkpoint inhibitors.

In this review, we aim to provide a comprehensive and critical synthesis of the emerging field of cancer neuroscience. We systematically examine how the nervous system regulates tumor progression through four core mechanisms: (1) direct neuron-tumor synaptic communication, (2) paracrine signaling via neurotransmitters and neuropeptides, (3) Schwann cell-mediated regulation, and (4) neuro-immune interactions. We also discuss how neurotransmitter signaling activates pro-malignant pathways in cancer cells and how the nervous system shapes the immune microenvironment, predominantly toward immunosuppression by modulating T cells, natural killer cells, macrophages, and myeloid-derived suppressor cells, thereby facilitating immune evasion and treatment resistance. Finally, we review emerging therapeutic strategies targeting neural regulation, including neurotransmitter receptor blockers, denervation techniques, neuromodulation devices, and approaches to remodel the immune landscape through neural signals. By integrating recent advances, this review establishes a conceptual framework for understanding neural regulation of cancer and guides future research and clinical translation in this rapidly evolving field.

Established mechanisms of neural regulation in driving malignant tumor progression

Tumor cell proliferation and migration determine recurrence risk and metastasis, from local infiltration to vessel invasion. The nervous system actively guides tumor proliferation and migration in the tumor microenvironment. Neuronal activity promotes tumor progression through direct neuron-tumor interactions and immune system modulation [2, 3, 5]. Multiple pathways - from neurotrophic chemotaxis to Schwann cell guidance, axon guidance molecule hijacking, neuroinflammation, and direct neuronal mitochondria hijacking - enable malignant tumor evolution. This section examines how the nervous system controls tumor behaviors, including proliferation, migration, therapeutic resistance, and metastasis (Fig. 1).

Fig. 1.

Diagram of the pathways and mechanisms of neural regulation of tumors. Firstly, tumors can form synaptic or synapse - like structures with neurons, thereby influencing tumor cell proliferation and invasion. Presynaptic neurons release glutamate, which binds to AMPA receptors (AMPARs) on the surface of tumor cells, which can further activate key downstream proliferative signaling pathways directly driving tumor cell proliferation and invasion upper left). Besides, non-brain tumors (such as breast cancer) can form “pseudo-tripartite synapses”, in which tumor cells do not form classic direct synapses with neurons but are located near healthy neuron-astrocyte synapses, receiving glutamate signals from the microenvironment through NMDA receptors (NMDAR) on their surface, thereby driving tumor colonization and progression top center). Cholinergic axonal terminals form typical synaptic structures with GBM cells, and the acetylcholine released by the presynaptic neurons promotes GBM progression through the muscarinic receptor (CHRM3) (upper right). Classical neurotransmitters such as glutamate, acetylcholine, and norepinephrine, as well as neuropeptides like CGRP and Substance P, regulate tumor cell proliferation through non-synaptic paracrine mechanisms. These molecules activate specific receptors on cancer cells, initiating downstream signaling cascades and thereby directly promoting tumor growth (bottom left). During tumor progression, cancer cells acquire the ability to evade immune surveillance, thereby escaping recognition and elimination by the host immune system. Acetylcholine can upregulate the expression of the immune checkpoint molecule PD-L1 on the surface of tumor cells, thereby enhancing tumor resistance to CD8 + T-cell cytotoxicity and promoting tumor cell survival and proliferation. Similarly, activation of GABAB receptors in cancer cells inhibits glycogen synthase kinase 3β (GSK-3β) activity and promotes tumor cell proliferation. The neurotrophic factor MDK stimulation leads CD8 + T cells to upregulate the expression of pro-inflammatory chemokine C–C motif chemokine ligand 4 (CCL4), impairing the ability to effectively recognize and eliminate tumor cells

Direct neuron-tumor interactions

The direct functional synaptic connections between the nervous system and glioma cells provide rapid growth signals to tumors, a critical discovery in cancer neuroscience. In 2019, two independent studies established that gliomas integrate into neural circuits through bona fide chemical synapses. Monje’s group demonstrated that neuronal activity increased extracellular potassium, inducing glioma depolarization, and identified both glutamatergic synapses and non-synaptic potassium currents between neurons and glioma cells [6]. Venkataramani et al. confirmed these findings, showing that neuro-glioma synapses exhibit typical ultrastructure on tumor microtubes and generate AMPA receptor-mediated postsynaptic currents [7]. Compared to the work by Michelle Monje group, Venkataramani’s research also reveals the important trafficking role of intracellular calcium signaling within the tumor-microtubule-glioma network through the combination of electrophysiological recordings and optogenetic approaches. It established that gliomas are not merely passive recipients of neural signals but are actively integrated into brain neural circuits [7]. Beyond local glutamatergic input, long-range cholinergic innervation also regulates glioma progression. Yang et al. and Sun et al. independently showed that basal forebrain cholinergic neurons form direct synapses with glioblastoma cells via CHRM3 receptors, enhancing tumor cell migration. Glutamatergic and cholinergic signals converge on calcium transients but diverge in transcriptional control, with dual blockade producing additive anti-tumor effects [8, 9].

This deadly communication is not unique to brain tumors, but exists in other malignant solid tumors. Ren et al. found that pancreatic ductal adenocarcinoma (PDAC) forms a “glutamatergic false synapse” between sensory nerve endings and cancer cells. At these synaptic points, cancer cells selectively enrich the NMDA receptor subunit GRIN2D (GluN2D), enabling them to respond to glutamate released by neurons, thereby promoting tumor growth and progression. In animal models, interference with this glutamate-GRIN2D signal can significantly improve the survival rate [10]. In breast cancer brain metastases, tumor cells establish “pseudo-tripartite synapses” adjacent to neuron-astrocyte synapses, co-opting neuronal glutamate to drive progression through NMDA receptors [11]. This finding establishes that brain metastatic cells co-opt the existing neuronal microenvironment for growth, presenting a rationale for targeting NMDAR signaling in brain metastasis patients. Importantly, this mechanism explains the clinical observation that certain breast cancer subtypes show preferential metastasis to the brain and suggests that NMDAR antagonists could have therapeutic value. Two independent studies have substantially advanced our understanding of neuron-SCLC interactions. Savchuk et al. demonstrated that vagus nerve transection inhibits primary SCLC growth, and SCLC cells form functional synapses with vagus nerves that exhibit depolarizing currents and calcium transients [12]. Concurrently, Sakthivelu et al. confirmed that SCLC cells can form functional synapses and receive both NMDA receptor- and GABA_A receptor-mediated synaptic inputs. Notably, both studies identified clinically available agents which destroy synapse and reduce SCLC tumor burden [13].

Despite the compelling pro-tumorigenic role of direct synapses described above, several lines of contradictory and context-dependent evidence warrant attention. First, GABAergic signaling exhibits striking context dependency. While the SCLC studies reported that GABAergic inputs promote tumor growth, other studies have shown that GABA can exert anti-proliferative effects in certain glioma subtypes. Second, the functional relevance of synapse formation in peripheral tumors remains incompletely validated. While electrophysiological and ultrastructural evidence exists for neuron-glioma synapses, the evidence for “pseudo-synapses” in pancreatic cancer and breast cancer brain metastases relies primarily on receptor expression, calcium imaging, and functional pharmacological perturbations. Definitive proof of bona fide synaptic ultrastructure (e.g., electron microscopy showing pre- and postsynaptic specializations) in these peripheral contexts is still lacking. Whether these represent true chemical synapses or more loosely defined paracrine signaling compartments is an open question that requires further investigation. Third, the effect of synaptic signaling may depend on tumor stage and molecular subtype. Most studies have been conducted in established, often late-stage, tumors. Whether direct synapses contribute to tumor initiation, early progression, or metastatic colonization is unknown. Furthermore, the expression of synaptic machinery components (e.g., AMPA receptors, NMDA receptors, CHRM3) varies substantially across tumor subtypes, and the correlation between receptor expression levels and clinical outcomes remains inconsistent across published datasets.

Though pharmacological blockade of these synaptic signals with AMPA receptor antagonists, muscarinic receptor inhibitors, or NMDA receptor modulators holds promise, therapeutic targeting of synaptic signals faces unresolved challenges. While AMPA receptor antagonists (e.g., perampanel), NMDA receptor antagonists, and anticholinergic agents show preclinical efficacy, the field has not yet established whether these effects are tumor-cell-autonomous versus mediated through broader neural circuit modulation. More importantly, some evidence suggests that AMPA receptor activation may also produce excitotoxicity in tumor cells, raising the possibility that the therapeutic effect depends on drug concentration, receptor subunit composition, and the baseline activity state of the tumor [7–9]. Radin (2025) comprehensively addressed this disparity, noting that the dual potential of AMPAR modulation (proliferation vs. excitotoxicity) warrants further investigation before clinical translation [14]. Notably, because these drugs may not readily cross the blood-brain barrier, they offer a potentially wide therapeutic window with minimal central nervous system side effects when targeting peripheral tumors [11].

In summary, the convergence of evidence across glioblastoma, pancreatic cancer, breast cancer brain metastases, and small cell lung cancer establishes that direct neuron-tumor synaptic communication is a conserved pro-tumorigenic mechanism. This represents a fundamental shift from viewing neural influences as indirect paracrine effects to recognizing active synaptic integration. However, rather than a universal pro-tumorigenic principle, the effect of synaptic signaling depends on the receptor subunit composition expressed by the tumor cell, the tumor stage and molecular subtype, and the balance between direct synaptic effects and indirect circuit-level modulation.

Future research should systematically map these contextual factors across tumor types, validate the ultrastructure of peripheral neuron-tumor contacts, and develop strategies that selectively disrupt pathological synapses while preserving normal neural communication. Identifying biomarkers will be essential for patient selection in future clinical trials of synaptic signaling inhibitors.

Paracrine signaling: neurotransmitters, neuropeptides, and neurotrophic factors

If the synapse formed between neurons and cancer cells is a dedicated circuit for direct conversational calls, then neurotransmitters and neurotrophic factors constitute a broader and more complex “wireless communication network” in the tumor microenvironment. In addition to direct synaptic connections, these signal molecules secreted by neurons or tumor cells have been proven to regulate tumor proliferation, invasion and metastasis process in various tumors, forming another extremely important pathogenic mechanism.

Glutamate

As the principal excitatory neurotransmitter, glutamate signals via both synaptic and paracrine pathways. Tumor cells release large amounts of glutamate through the cystine/glutamate antiporter (Xc- system), activating AMPA and NMDA receptors to promote proliferation and inducing neuronal hyperexcitability, which contributes to tumor-associated epilepsy [15]. In lung cancer, tumor cells interact with astrocytes; metabotropic glutamate receptor 1 (mGluR1) receives astrocyte-secreted glutamate, activating mGluR1 to enhance EGFR interaction and facilitate brain metastasis [16]. In pancreatic ductal adenocarcinoma, glutamatergic false synapses between sensory nerve endings and cancer cells increase glutamate sensitivity, promoting invasion and metastasis [10, 17]. These findings suggest that targeting glutamate signaling may offer a novel anti-tumor strategy. However, glutamate signaling has context-dependent duality: in certain glioma subtypes, high glutamate levels induce excitotoxicity and cell death, depending on receptor composition, concentration, and metabolic state [7, 15, 18]. Moreover, the therapeutic use of glutamate signaling inhibitors must balance efficacy against central nervous system side effects due to broad suppression of physiological excitatory transmission.

Acetylcholine (ACh)

Acetylcholine is an important neurotransmitter that can promote the progression of brain tumors, especially glioblastoma. Acute ACh stimulation induces sustained calcium oscillations and transcriptional reprogramming of glioblastoma cells into a motile state via CHRM3 [8]. Beyond brain tumors, ACh also plays key roles in peripheral tumors. In prostate cancer, ACh released by parasympathetic nerves promotes cancer cell invasion and lymph node metastasis through CHRM1 [19]. In gastrointestinal cancer, cholinergic signals activate the Wnt signaling pathway in tumor stem cells through CHRM3, thereby promoting tumorigenesis [20, 21]. Besides, in gastric cancer cells, Ach released by infiltrating vagus nerves upregulates the lipase ABHD16A, facilitating the production and secretion of the metabolite lysophosphatidylserine (LysoPS) into the tumor microenvironment, which in turn promotes the proliferation of group 3 innate lymphoid cells (ILC3s) and induces the production of IL-22, which enhance immune resistance [22]. Tumor cells themselves can synthesize and secrete ACh, activating muscarinic or nicotinic receptors in an autocrine manner to enhance proliferation, migration, and immune evasion [23]. However, cholinergic signaling is not uniformly pro-tumorigenic; its effects depend on the balance between muscarinic and nicotinic receptor expression, which varies across tumor types and stages. This heterogeneity complicates therapeutic targeting, as broad cholinergic blockade may yield unpredictable outcomes.

Norepinephrine (NE)

As a core neurotransmitter of the sympathetic nervous system, NE binds to and activates β2-AR on tumor cells or immune cells in the microenvironment, promoting tumor cell cycle process and upregulating pro-inflammatory factors, establishing an immunosuppressive microenvironment [24, 25]. In ovarian cancer, NE upregulates the expression of human telomerase reverse transcriptase (hTERT), promoting epithelial-mesenchymal transition (EMT) [26–28]. NE also exhibits pro-migration competency in prostate cancer and digestive system cancers [29–31]. NE can also activate β2-AR on endothelial cells, reprogramming their metabolism towards aerobic glycolysis to promote angiogenesis within the tumor microenvironment [32]. Research shows that social interaction regulates anti-tumor immunity by suppressing sympathetic nerve activity and norepinephrine release in tumors [33].

The role of sympathetic signaling exhibits striking stage dependency. Several studies have shown that sympathetic nerves are protective during early tumorigenesis, with denervation accelerating tumor initiation in certain models [32, 34, 35]. This suggests a functional switch from early protective to late pro-tumorigenic roles, the molecular mechanisms of which remain poorly understood. Both clinical epidemiological data and prospective clinical trials suggest that the use of β-blockers (such as propranolol) may improve cancer patient prognosis and exert synergistic effects with immune checkpoint inhibitors [36, 37].

γ-Aminobutyric Acid (GABA)

As the principal inhibitory neurotransmitter, GABA exhibits striking duality and context dependence in tumors. In head and neck squamous carcinoma (HNSCC), GABA upregulates cyclin D2 and BCL2-like 1 to promote tumor survival and growth [38]. In pancreatic cancer, GABA activates GABAA receptors, driving the p38 MAPK and Ca^{2 +} -NF-κB pathways while recruiting pro-tumorigenic macrophages [39]. In colorectal cancer and breast cancer brain metastases, tumor cells upregulate glutamate decarboxylase to enhance GABA production, thereby promoting proliferation [40, 41]. In hepatocellular carcinoma (HCC), GABA directly binds to and stabilizes β-catenin, activating Wnt/β-catenin signaling and enhancing metastasis [42]. In non-small cell lung cancer (NSCLC), elevated GABA levels accelerate malignant progression and brain metastasis. However, during NSCLC radiotherapy, GABAA receptor activation induces GABARAP polymerization and stabilizes the mitochondrial receptor Nix, triggering selective autophagy, suppressing brain metastasis, and enhancing chemoradiotherapy efficacy [43, 44]. Additionally, GABA exerts anti-proliferative effects in certain glioma subtypes [45, 46]. This complexity, where GABA is pro-tumorigenic under basal conditions but anti-tumorigenic under therapeutic stress, makes targeting the GABAergic system particularly challenging. The effect likely depends on the balance between GABAA and GABAB receptor expression, the chloride transporter profile (NKCC1 vs. KCC2), and the presence of concurrent therapeutic stressors [47–50].

Neurotrophic factors

Neurotrophic factors play a more foundational and diverse role in regulating malignant tumor behaviors. BDNF and NGF establish foundational regulatory axes that promote perineural invasion and neuronal recruitment in liver, pancreatic, gastric and epithelial ovarian cancers [51–57]. Exogenous BDNF drives HepG2 cell migration and invasion via TrkB in a concentration-dependent manner. Stromal cells within the tumor microenvironment serve as a key source of BDNF, secreting BDNF to guide axon growth toward tumors and thereby enabling perineural invasion [51]. The NGF/TrkA axis also critically regulates tumor invasion. In triple-negative breast cancer, NGF triggers sensory neurons to secrete CGRP, activating cancer-associated fibroblasts to produce collagen that excludes immune cells [58]. In gastric cancer, NGF overexpression promotes enteric neuron expansion and carcinogenesis [52]. In pancreatic cancer, NGF is positively correlated with the degree of tumor malignancy and participates in the regulation of neuronal axon growth towards the tumor, providing experimental clues for NGF -mediated tumor perineural invasion [53–55]. In addition, the NGF/TrkA signaling pathway exhibited strong transcriptional regulation competency, thereby regulating the invasion and metastasis of cancer cells [57]. However, the role of neurotrophic factors is context-dependent: TrkA activation can induce differentiation and growth arrest in certain neuroblastoma models [59, 60]. These opposing effects likely depend on the presence of co-receptors, downstream adaptor protein recruitment, and the cellular differentiation state [61].

Neuropeptides (such as CGRP, substance P/SP)

Calcitonin gene-related peptide (CGRP) is a neuropeptide released by sensory neurons that plays a key role in pain transmission and immune modulation. Sensory neuron-derived neuropeptides play a key role in the neuro-immune-tumor axis. CGRP inhibits CD8+ T cell activity and infiltration via RAMP1 in melanoma and oral cancer, thereby impairing antitumor immunity [62, 63]. In gastric cancer models, CGRP levels are elevated, promoting tumor growth and metastasis via the CGRP-RAMP1 axis [64]. Recent evidence from oral squamous cell carcinoma (OSCC) provides deeper mechanistic evidence that CGRP-expressing sensory nerves link tumor-associated pain to immunosuppression via efferent CGRP release. It directly reinforces the CGRP-RAMP1 immunosuppression axis [65]. CGRP receptor antagonism slows tumor growth and improves anti-tumor immunity. Targeting CGRP may serve as a potential therapeutic strategy in OSCC to reduce pain and improve therapeutic response [65]. In triple-negative breast cancer (TNBC), CGRP and substance P (SP) are the predominant neuropeptides, driving an immune-excluded microenvironment via dense extracellular matrix formation [58].

Substance P (SP) is a neuropeptide predominantly released from sensory nerve endings, where it functions as a key mediator of neurogenic inflammation and pain transmission [66]. Recently, studies have revealed that neuronal substance P drives metastasis through the extracellular RNA–TLR7 axis [67]. The study found that highly metastatic breast cancer cells recruit sensory nerve through SLIT2. These “hijacked” sensory nerves release substance P, which binds to TACR1 receptor, inducing cell death and RNA release, which then activates paracrine TLR7 signaling to enhance metastatic gene expression [67]. SP also activates MAPK and upregulates MMP9 to increase invasiveness [68]. However, sensory neuron functions are context-dependent. Early capsaicin-ablation studies suggested an antitumor role of sensory nerves, attributed to loss of pro-inflammatory neuropeptides like SP [67, 69]. It is important to note that sensory neurons exhibit functional duality. While they can initiate systemic anti-tumor reflexes (e.g., through pain signaling), within the local tumor microenvironment [17], specific neuropeptides often exert potent immunosuppressive effects, promoted breast tumor growth, invasion and metastasis. Identifying which subsets dominate in particular tumor contexts is essential for developing effective therapeutic strategies [69].

Zhang et al. (2026) identified a novel paracrine mechanism by which the peritumoral microenvironment drives nerve-cancer interactions in PDAC. CD4⁺ T cell-derived IL-22 triggers peritumoral acinar cells to secrete regenerating islet-derived (Reg) proteins, which activate EXTL3 signaling on both cancer cells and neurons. In PDAC cells, Reg-EXTL3 promotes invasiveness along nerves via autocrine TGF-β, while in neurons, it enhances axonal growth and excitability, leading to hyperinnervation and pain. This study reveals a quadripartite immune-stromal-neural-cancer network and identifies the Reg-EXTL3 axis as a potential therapeutic target that could simultaneously inhibit tumor progression and alleviate cancer pain [70].

Collectively, the evidence establishes that neurotransmitter and neuropeptide signaling profoundly influences tumor progression. However, the field must move beyond a simplistic “pro-tumorigenic” narrative toward a more nuanced context-dependent model. The effect of targeting a given neurotransmitter system will depend on which receptor subtypes are predominantly expressed by tumor cells, immune cells or stromal cells. The field lacks systematic mapping of receptor expression profiles across tumor types, stages, and microenvironments. Finally, most current evidence remains correlative or derived from preclinical models, and functional validation in human tissues is urgently needed before clinical translation of these promising therapeutic strategies.

The complex regulatory effects of these signaling molecules on immune cells within the tumor microenvironment will be discussed in detail in the following chapter.

The role of Schwann cells in tumor

Schwann cells, key glial cells of the peripheral nervous system, play complex roles in tumors. Studies show that in pancreatic cancer, oral squamous cell carcinoma and distal cholangiocarcinoma, Schwann cells are recruited by tumor cells and play a multifaceted role in promoting PNI and migration through a series of mechanisms, creating an immunosuppressive environment. Single-cell technologies have revealed Schwann cell heterogeneity in tumors. Min-Min Chen et al. identified a TGFBI+ Schwann cell subgroup at nerve invasion edges. These cells, activated by TGF-β, secrete pro-migration factors and participate in ECM remodeling, mapping a spatial cell atlas of PDAC nerve invasion [71]. Cancer cells reprogram Schwann cells into a “tumor-activated” state, forming micro-channels called tumor-activated Schwann cell tracks (TASTs), which guide tumor cell migration [71]. Research showed that tumor cells with high ITGA5 expression reprogram the Schwann cells by binding to fibronectin (FN1), increasing NGF secretion. This suppresses natural killer cells and IFN-γ release, creating an “immune-privileged” zone [72].

Beyond their role in stromal reprogramming, Schwann cells are also directly regulated by tumor-derived factors that promote perineural invasion. Zhang et al. identified group-specific component protein (GC) as one of the most significantly upregulated genes related to PNI, primarily derived mediator that activates Schwann cells by inducing a dedifferentiation program and enhances the mutual chemoattraction between PDAC cells and Schwann cells via integrin β1 (ITGB1)-FAK signaling [73]. Importantly, Schwann cells are not merely passive responders; they also actively secrete axon guidance molecules such as Netrin-1, which is mainly expressed in Schwann cells and promotes their own proliferation and migration by binding to various receptors [74–76]. Hiroki Kobayashi et al. demonstrated that cancer cells can hijack Netrin-1 signaling through their NEO1 receptor to further drive tumor growth. Netrin-1 promotes sympathetic axonogenesis through neuronal NEO1 and, in parallel, enhances cancer cell stemness and EMT via NEO1-mediated FAK activation [77]. Autophagy in Schwann cells promotes perineural invasion through the NGF/autophagy-related gene (ATG) pathway [55]. Schwann cell-derived CXCL5 upregulates EMT-related proteins in lung cancer cells, promoting metastasis [78].

In distal cholangiocarcinoma, spatial transcriptomics has further illuminated the microenvironmental remodeling associated with PNI, providing a subcellular atlas that contextualizes these cellular interactions [79]. Collectively, these findings demonstrated that Schwann cells are active participants in the tumor microenvironment, forming TGFBI+ subpopulations and TAST micro-channels that facilitate cancer cell invasion, migration, and immune escape through various mechanisms. Tumor-derived factors further reprogram Schwann cells, while Schwann cells themselves secrete factors to promote neural-tumor crosstalk and immune evasion.

Despite the established pro-tumorigenic roles of Schwann cells, several critical knowledge gaps remain. First, the functional heterogeneity of Schwann cells in the tumor microenvironment remains poorly characterized; it is unknown whether certain subpopulations exert anti-tumorigenic or protective functions. Second, most evidence is correlative or from in vitro studies; in vivo loss-of-function validation is lacking. Third, the temporal dynamics of Schwann cell recruitment during tumor initiation vs. progression have not been elucidated. Fourth, therapeutic targeting of Schwann cells may impair their essential physiological functions in nerve maintenance and repair. Future research should focus on single-cell and spatial transcriptomic mapping of Schwann cell subpopulations across diverse cancer types and stages and investigating the temporal dynamics of Schwann cell recruitment during tumor progression. Development of selective targeting strategies that spare physiological Schwann cell functions; and exploration of Schwann cell-derived signals as predictive biomarkers for perineural invasion and patient prognosis will be essential to determine whether Schwann cells represent a viable therapeutic target in cancers with prominent neural tropism.

The role of CAFs in neuro-tumoral regulation

Studies on the tumor microenvironment have revealed a complex regulatory network composed of neural, immune, and stromal elements. Cancer-associated fibroblasts (CAFs) have emerged as central architects of a tumor-permissive microenvironment, yet their specific role in orchestrating the bidirectional crosstalk between the nervous system and the immune system has come into focus. Wang et al. demonstrated that nociceptive neurons activate CAFs, which suppresses CAF-derived IL-15 secretion and thereby impairs NK cell antitumor activity, establishing a pro-tumorigenic neural–stromal–immune axis [80]. Recently, Jérémy Nigri et al. revealed that myofibroblasts orchestrate bidirectional cross-talk with sympathetic neurons, secreting axon guidance molecules to promote nerve infiltration in inflamed and neoplastic pancreatic tissues. Specifically, α1-adrenoreceptor activation in fibroblasts acts as a molecular switch that amplifies pancreatitis severity and accelerates tumor growth, revealing new paracrine interactions for further therapeutic development [81]. Furthermore, CAFs have been shown to acquire neuronal gene expression programs and exhibit multicellular calcium waves, which contributes to physical barrier formation and subsequent T cell exclusion. Pan-cancer analyses further corroborate a significant correlation between neural signals, CAF infiltration, and immune exclusion [82]. A spatially resolved atlas comprising a total of 20 cell types was generated, uncovering enrichment of Schwann cells, type 2 conventional dendritic cells (cDC2), M2-like macrophages, cancer associated fibroblasts (CAFs) and B/plasma cells in PNI-high tumors, along with depletion of exhausted CD8+ T cells. Spatial mapping further revealed distinct PNI-associated niches, notably matrix-producing CAFs (mCAFs)-macrophage clusters exhibiting coordinated enrichment of inflammatory and fibrotic programs [79].

Despite these advances, critical questions remain unresolved, including how CAF heterogeneity dictates their interactive preferences with distinct neuronal subtypes and whether targeting neuro–CAF crosstalk perturbs normal tissue homeostasis [58, 83]. Future research should prioritize the spatial and molecular characterization of CAF subset-specific neuroreceptor profiles, and evaluate combinatorial strategies integrating neuroactive agents—such as CGRP receptor antagonists—with immune checkpoint inhibitors to achieve precision intervention.

Tumor cells mimic neural structures and hijack resources

The physical contact between tumor cells and nerves actively drives tumor progression. Tumor cells receive signals and construct networks, even stealing energy factories from neurons to enhance metastatic competency. Tumor cells form membrane structures like tumor microtubules (TMs) and tunneling nanotubes (TNTs), allowing the exchange of molecules, RNA, and organelles over distances to promote invasion and therapeutic resistance. In gliomas, TM formation relates to neuron proteins GAP-43 and Ttyh1 [84]. However, cancer cells not only build their own network and communicate with nerves, but also actively disrupt nerve structures, thereby forming a tumor microenvironment that is beneficial to themselves. In glioblastoma, tumor cells damage axons in brain white matter, activating SARM1-mediated Wallerian degeneration and axonal death, triggering neuroinflammation that promotes tumor growth. Suppressing SARM1 can delay tumor progression [85, 86]. The destruction of neural structures by cancer cells is not limited to promoting cancer but also directly affects the therapeutic response. In addition to direct axonal injury, cancer cells can directly destroy the myelin sheath structure of the nerves, resulting in cancer-induced nerve injury. In patients with cutaneous squamous cell carcinoma, melanoma, and gastric cancer, perineural invasion of tumor-associated nerves and CINI are associated with adverse reactions and drug resistance to anti-PD-1 therapy [87]. Therefore, the effect of tumor treatment can be improved by denervating the tumor, conditionally knocking out the transcription factor (Atf3) that mediates injury signals in neurons, knocking out interferon-α receptor signaling (Ifnar1-/-), or using anti-PD-1 in combination with anti-IL-6 receptor blocking agents [87].

Another striking study revealed that cancer cells can “steal” healthy mitochondria from neurons using nanotube-like structures. This “energy supply” enhanced cancer cells’ metabolic competency and resistance to stresses like oxidative stress and shear force during metastasis. In a breast cancer brain metastasis model, the proportion of cancer cells with stolen mitochondria in brain metastases was higher than that in the primary site, showing that direct energy transfer is essential for tumor metastasis and colonization [84]. Cancer cells view the nervous system as a “resource-setter” to exploit. They establish communication pathways with the nervous system and disrupt axons to create a favorable inflammatory microenvironment. Tumors also steal neurons’ energy factories (mitochondria), challenging the view that nerves are passive victims. These findings offer new insights for anti-cancer therapy.

The neuro-immune-tumor axis regulate tumor progression

Paracrine signaling as core messengers in the neuro-immune-tumor axis

Neurons and the immune system respond to each other through signaling molecules to form a precise regulatory network. In cancer research, the crosstalk between neurons, immune cells, and cancer cells can profoundly affect cancer progression, gradually becoming a key to understanding the tumor immune microenvironment, anti-tumor immunity, and immunotherapy.

In addition to directly acting on tumor cells, the nervous system more profoundly engages in dialogue with immune cells by releasing a diverse array of neurotransmitters and neuropeptides that act on immune cells expressing the corresponding receptors, thereby systemically shaping the tumor immune microenvironment. The nervous system regulates the trafficking, function, and immune response of different immune cell subsets through multiple pathways, ultimately influencing tumor initiation and progression. The following sections will detail how these neural signals modulate specific immune cell populations, including regulatory T cells, tumor-associated macrophages, natural killer cells, and neutrophils, to orchestrate anti-tumor immunity or promote immune evasion [2, 3] (Fig. 2).

Fig. 2.

Tumor modulation via the neuro-immune-tumor axis. Norepinephrine, derived from sympathetic nerves, activates β2-AR on regulatory T cells, Tregs, triggering the cAMP/PKA signaling pathway, enhancing the migration of Tregs to the tumor microenvironment, and producing multiple immunosuppressive effects (upper left). Nociceptive neurons release CGRP, which interacts with the CGRP receptor components RAMP1 and CALCRL on the surface of CAFs, thereby inhibiting the production of IL-15 by CAFs. This in turn weakens the recruitment and effector functions of NK cells, impairs tumor immune surveillance, and promotes tumor progression (lower left). Neuron released neurotransmitters promotes the transformation of the tumor-associated macrophage count in the tumor microenvironment towards an immunosuppressive phenotype (upper right). Sympathetic nervous system released adrenergic activates β-adrenergic receptors on tumor cells, inducing an increase in SP1 levels in tumor-derived exosomes, SP1 binds to TLR4 on neutrophils, leading to the secretion of IL-1β by neutrophils. Subsequently, IL-1β promotes cancer metastasis by synergistically activating the EGFR (lower right)

Neuro-Treg-cancer pathway

The sympathetic nervous system shapes the tumor immune landscape by modulating regulatory T cells (Tregs), creating an immunosuppressive microenvironment that enables cancer progression. Through norepinephrine release, sympathetic nerves engage β2-adrenergic receptors (β2-AR) on immune cells, triggering the cAMP/PKA pathway, enhancing Treg migration to the tumor microenvironment, and producing immunosuppressive effects [88]. NE regulates MDSCs, upregulates PD-1 expression on T cells, and leads to T-cell functional exhaustion [89], altering MDSC profiles through bone marrow innervation (Fig. 2) [90]. In melanoma, CGRP promotes CD8+ T-cell exhaustion, impairing immunity and facilitating tumor growth. CGRP inhibition can restore anti-tumor immunity [62]. Acetylcholine upregulates PD-L1 expression on tumor cells, enhancing their resistance to CD8+ T cells [91]. Recently, Wen HZ et al. showed that social interaction inhibits tumor sympathetic nerve activity, reducing Treg and MDSC infiltration while increasing CD4+ and CD8+ T cells [92], as validated in both mouse models and human samples. GABAB receptors reduce CCL4 and CCL5 expression and secretion in carcinoma colon cells, decreasing T lymphocyte tumor infiltration. GABA from B lymphocytes signals through GABAA receptors on CD8+ T lymphocytes, attenuating cytotoxic T cell responses and promoting tumor growth [93]. The study by Zhang et al. from 25 PDAC patients indicated that low nerve infiltration areas are surrounded by tertiary lymphoid structures with effector memory CD8+ T cells, B cells, and plasma cells, indicating anti-tumor immune responses. High nerve infiltration areas are associated with the accumulation of regulatory T cells, indicating a role for neural signals in promoting Treg-mediated immunosuppression [71].

Neuro-TAM-cancer pathway

Tumor-associated macrophages (TAMs) serve as key mediators in neural regulation of cancer progression, with research revealing signaling mechanisms connecting neuronal activity to macrophage function. In the tumor microenvironment, macrophages and sensory nerves establish proximity that enables their functional interaction. NE inhibits tumor-associated macrophages to release pro-inflammatory cytokines, weakening anti-tumor immune responses and promoting tumor progression [94]. Recently, Yu Z et al. revealed that cancer cells under TAM pressure secrete SLIT2 through ATF4-dependent mechanism, activating sensory neurons and initiating pain signaling [95]. Breast cancer cells secrete arginine to reprogram TAM, activating the polyamine which transform macrophages to immunosuppressive M2 phenotype through thymine DNA glycosylase activation [96]. This neural activation represents one aspect of neuro-immune dialogue in cancer. Beyond neural interactions, small-molecule therapies have emerged as promising approaches to modulate TAM polarization and reprogram immunosuppressive milieu, particularly in challenging malignancies like glioma [97]. The therapeutic potential of targeting TAMs extends to pancreatic cancer, where spatial multi-omics research shows Schwann cells at neural invasion fronts transform into TGFBI⁺ phenotype that recruits inflammatory monocytes via CCL2 secretion. These monocytes differentiate into cathepsin B-expressing macrophages that suppress NK cell function [71]. This cellular network creates an immunosuppressive niche linked to poor patient outcomes, suggesting interventions targeting Schwann cell reprogramming could reverse immunosuppression.

Neuro-NK cell-cancer pathway

NK cells play a crucial role in innate immunity, responsible for identifying and eliminating malignant cells [98]. Natural killer cell function is regulated by neural signaling pathways, with sensory neurons suppressing NK activity in the tumor microenvironment. Wang et al. found that nociceptive neurons release CGRP, which interacts with RAMP1 and CALCRL on CAFs, inhibiting IL-15 production. This weakens NK cell recruitment and functions, impairs immune surveillance, and promotes tumor progression and cancer pain (Fig. 2) [2, 3, 80]. Blocking the CGRP receptor with Rimegepant recovers NK cell activity and suppresses tumors in preclinical studies [80]. IL-15 signaling importance extends beyond pancreatic cancer, as tumors deploy strategies to compromise NK cell responsiveness to this cytokine [99]. This study found that tumor cells use UBE2F and ARIH1 genes to mediate IL-15 receptor degradation, desensitizing NK cells to IL-15 stimulation [99]. Genetic interruption of this pathway through CRISPR-Cas9 knockout enhances IL-15 R (CD122) expression, potentiating NK cell cytotoxicity, cytokine production, and resistance to tumor-derived immunosuppressive factors. This approach shows promise when combined with CAR-NK therapies, addressing NK cell exhaustion in adoptive cell transfer protocols.

Neuro-neutrophil-cancer pathway

Neutrophils have emerged as significant contributors to cancer progression under neural influence, particularly in conditions of chronic stress where sympathetic activation initiates a cascade of events promoting metastatic dissemination. Under chronic stress conditions, β-adrenergic receptors on tumor cells were activated, inducing an increase in SP1 levels in tumor-derived exosomes (TDES) [100]. SP1 binds to TLR4 on neutrophils and activates the TLR4/NF-κB signaling pathway, leading to the secretion of IL-1β by neutrophils. Subsequently, IL-1β promotes cancer metastasis by synergistically activating the EGFR-dependent PI3K/AKT and IL-1 R-dependent MEK/ERK signaling pathways in tumor cells (Fig. 2) [100, 101].

Beyond stress-mediated activation, recent research has revealed that neutrophils display remarkable functional plasticity in cancer. A recent study identified a specific peripheral blood neutrophil subpopulation expressing high level of immunosuppressive CD244 and type 2 immune response signal IL4Ra, present in solid tumors [102]. This conserved neutrophil signature suggests potential common therapeutic targets for modulating neutrophil function in cancer. The findings underscore neutrophils as integrated responders to neural stress signals and promising targets for interrupting neuro-immune mediated cancer progression.

Beyond the primary neurotransmitters and neuropeptides detailed in the main text, the neuro-immune-tumor axis involves a broader spectrum of signaling molecules, including Neuropeptide Y (NPY), Vasoactive Intestinal Peptide (VIP), amphiregulin, ATP, serotonin, and dopamine. The Table 1 summarizes key neuroactive molecules, their immune targets, and documented effects within the tumor microenvironment.

Table 1.

Key neuroactive molecules, their immune targets, and roles in the tumor microenvironment

Neuroactive Molecule	Primary Immune Target(s)	Role in the Tumor Microenvironment	Tumor Type Specificity	Evidence	Reference
Acetylcholine	α7-nAChR (Macrophages, T cells)	Induces anti-inflammatory responses via the cholinergic pathway; suppresses IFN-γ production and immune surveillance.	Glioblastoma, non-small cell lung cancer, gastric cancer, hepatocellular carcinoma	In vitro, preclinical mouse models	[23, 103]
Glutamate	mGluR, NMDA, AMPA (T cells, MDSCs)	Promotes excitotoxicity and calcium dysregulation; impairs T cell metabolism, drives MDSC infiltration, and facilitates tumor progression.	Glioblastoma, melanoma, breast cancer	In vitro, rodent models	[104, 105]
GABA	GABAA, GABAB (T cells, NK cells)	Hyperpolarizes immune cells, inhibiting calcium influx; suppresses T/NK cell activation, cytotoxicity, and cytokine release.	Pancreatic cancer, colon cancer, breast cancer	In vitro, preclinical mouse models, some clinical association studies	[93, 106–108]
Dopamine	D1, D2 (T cells, NK cells, TAMs)	Exerts context-dependent dual effects; D1-like receptors may enhance immunity, while D2-like receptors typically suppress anti-tumor responses.	Glioblastoma, lung cancer	In vitro, in vivo (rodent)	[109–111]
Norepinephrine (NE)	β2-AR (Macrophages, T cells, MDSCs)	Activates the cAMP/PKA pathway; induces M2 macrophage polarization, T cell exhaustion, angiogenesis, and metastatic spread.	Breast cancer, ovarian cancer, prostate cancer	In vitro, preclinical mouse models, retrospective clinical data (β‑blocker use)	[89, 112, 113]
Substance P	NK-1 R (Macrophages, Endothelial cells)	Triggers NF-κB signaling; sustains chronic pro-tumor inflammation and enhances tumor cell migration and invasion.	Pancreatic cancer, breast cancer, glioblastoma	In vitro, mouse models	[114]
Calcitonin Gene-Related Peptide (CGRP)	CALCRL/RAMP1 (T cells, Macrophages)	Inhibits TCR signaling; suppresses cytotoxic T cell function and promotes an immunosuppressive myeloid cell phenotype.	Head and neck squamous cell carcinoma (HNSCC).	In vitro, preclinical models	[115]
Neuropeptide Y (NPY)	Y1, Y2, Y5 (Tregs, Macrophages)	Enhances Treg stability and function; suppresses anti-tumor immunity and promotes stromal remodeling.	Breast cancer, prostate cancer, neuroblastoma	In vitro, syngeneic/xenograft mouse models	[116, 117]
Vasoactive Intestinal Peptide (VIP)	VPAC1, VPAC2 (Dendritic cells, T cells)	Potently induces a tolerogenic DC phenotype; promotes Treg differentiation and inhibits antigen presentation.	Colon cancer, pancreatic cancer	In vitro, preclinical models, limited clinical studies	[118, 119]
Amphiregulin (AREG)	EGFR (Macrophages, Tumor cells)	Activates EGFR/MAPK signaling; promotes M2 macrophage polarization and supports tumor cell survival.	Squamous Cell Carcinoma.	In vitro (cell lines), in vivo (murine models), clinical association studies, and retrospective analyses of EGFR-targeted therapy.	[120]
Adenosine Triphosphate (ATP)	P2 X 7, P2Y2 (Dendritic cells, T cells)	Concentration-dependent: Low levels act as a “danger signal” to activate immunity; high levels promote immune cell dysfunction and death.	Melanoma, colorectal cancer (and other solid tumors)	In vitro, in vivo (rodent)	[121, 122]
Serotonin (5-HT)	5-HT2A, 5-HT7 (T cells, Myeloid cells)	Modulates T cell polarization; promotes Treg expansion and MDSC activity, suppressing Th1-mediated anti-tumor responses.	Colorectal, hepatocellular, pancreatic, breast, melanoma	In vitro, in vivo (rodent), clinical association (e.g., SSRI use)	[123–125]

Immune regulation by cancer induced neuron injury

Recent research achieved significant breakthroughs in mechanistic exploration and therapeutic translation of the neuro-immune-neoplasm axis, particularly in cancer-induced nerve injury (CINI), postoperative local immune activation, and spatial analysis of immune microenvironment in pediatric brain tumors. The study revealed that cancer cells can induce CINI by directly contacting and degrading nerve fiber myelin sheaths. Damaged neurons initiate a repair program centered on transcription factor ATF3 and secrete IL-6 and type I interferons, leading to chronic inflammation. This neurogenic inflammation remodels the tumor microenvironment, resulting in enrichment of immunosuppressive macrophages (CD68+CD163+PD-L1+) and exhaustion of CD8+ T cells, driving drug resistance to anti-PD-1 therapy. This can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade [87]. This study demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential. This contrasts with previous studies focusing on immunoregulatory roles of neurotransmitters like norepinephrine, providing new targets and combination strategies for reversing immune drug resistance.

It is important to emphasize that these findings do not challenge the critical role of surgical resection as the standard of care, nor do they suggest that nerve-sparing approaches should be avoided. Rather, they highlight a biological mechanism by which residual microscopic disease may interact with exposed neural tissue post-operatively, underscoring the potential need for adjuvant therapies targeting neural-tumor interaction pathways to complement, not replace, existing surgical and oncological treatments. A study explored implanting a biodegradable polymer brace into the glioblastoma resection cavity for controlled release of TLR7/8 agonist (resistimod). This approach enhances immunostimulatory effects induced by brain surgery, triggering innate immune inflammation within the postoperative window, promoting lymphocytic infiltration, achieving residual neoplasm clearance, and establishing long-term immune memory in mouse models. Compared with traditional postoperative regional chemotherapy, which primarily exerts cytotoxic rather than immune-activating effects [88], this strategy represents a shift from cell killing to immune microenvironment remodeling.

Tumor–brain crosstalk restrains cancer immunity via a sensory–sympathetic axis

How tumors manipulate neural circuits to evade immunity is unclear. In a recent study, Wei et al. revealed that in lung adenocarcinoma, a vagal sensory–brain stem sympathetic circuit that suppresses macrophages and CD8+ T cells via β2-adrenergic signaling [126, 127]. They demonstrated that lung tumors induce functional engagement of vagal sensory neurons expressing Npy2r. These afferent nerves transmit signals from the tumor microenvironment to brainstem nuclei, which in turn drive elevated sympathetic efferent activity back to the tumor site. This sympathetic output suppresses anti-tumor immunity specifically through β2-adrenergic receptor signaling in alveolar macrophages. Disruption of this sensory-to-sympathetic pathway significantly inhibited lung tumor growth by enhancing immune responses against cancer [126]. This study provides the first mechanistic evidence for a complete “tumor–brain–tumor” circuit that restrains cancer immunity, identifying the vagal sensory–sympathetic axis as a potential therapeutic target for visceral organ cancers.

Targeting the neural-immune axis for cancer therapy

In recent years, antineoplastic immunization therapies targeting the nervous system have achieved significant progress. Cell adhesion molecules, neurotrophic factors, and neurotransmitters secreted by neurons can regulate the growth and metastasis of neoplasms, making the regulation of neuronal secretion a potential antineoplastic strategy. The core goal of this strategy is to block specific neurotransmitter signals to disconnect the nutritional supply of neoplasms.

Anti-tumor strategies by blocking neurotransmitter signaling

Targeting neurotransmitter signaling pathways has emerged as a promising strategy for cancer treatment. The cholinergic signaling pathway is one of the most studied targets. Acetylcholine-mediated cholinergic receptor signaling drives carcinoma cell proliferation, invasion, and metastasis. Preclinical evidences showed that, both pharmacological inhibition and gene knockout of the muscarinic acetylcholine M3 receptor show inhibitory effects on neoplasms of the stomach, small intestine, and breast [128–130]. Drexler et al. revealed that long-range cholinergic nerve inputs from the basal forebrain and midbrain drive tumor growth in lethal GBM and diffuse midline glioma (DMG). These signals act through the muscarinic receptors M1R and M3R to promote tumor proliferation. In preclinical studies, anticholinergic drugs (such as scopolamine) can inhibit tumor progression [9, 131]. Botulinum toxin, which blocks acetylcholine release, has also been shown to inhibit tumor growth in murine cancer models, the precise mechanism of which remains to be fully elucidated [132]. Wang et al. demonstrated that in xenograft mouse models, blocking acetylcholine signaling with the receptor antagonist 4-DAMP reduced PD-L1 expression and the self-renewal capacity of CD133+ thyroid carcinoma cells [133]. However, no cholinergic-targeting drugs are currently FDA-approved specifically for cancer treatment based on this mechanism. The acetylcholinesterase inhibitor donepezil that used for Alzheimer’s disease has been associated with potential tumor-promoting effects in preclinical models, but this has not been systematically evaluated in cancer patients [9].

In addition to the cholinergic system, other neurotransmitters are important targets [91]. Similarly, chemical or genetic knockout of β2- and β3-adrenergic signaling in mouse models inhibits the growth and metastasis of neoplasms of the prostate [134].

Glutamatergic signaling plays a key role in neuroneoplasm communication. mGluR1 is essential for maintaining the tumorigenic phenotype. The glutamate release inhibitor riluzole inhibited MCF-7 breast cancer xenograft progression in mouse models [135]. Dual blockade of glutamatergic and cholinergic signaling showed synergistic therapeutic effects in GBM mouse models [9]. Riluzole is FDA-approved drug for amyotrophic lateral sclerosis (ALS) but not for cancer. No clinical trials have yet evaluated its efficacy as an anti-cancer agent based on glutamate signaling mechanisms [135].

Preclinical studies demonstrated that GABA acts through GABAA or GABAB receptors on tumor cells and impairs T-cell infiltration [106]. Sun et al. showed that in a breast mouse model, combining GABAB receptor agonist baclofen with anti–PD-L1 therapy enhanced immune response and tumor-suppressive effects [136]. Baclofen is FDA-approved for spasticity but no clinical trials have evaluated GABAergic agents for cancer treatment.

In August 2025, the FDA granted accelerated approval to Dordaviprone (Modeyso), the first drug for treating H3 K27M-mutant diffuse midline glioma [137]. As a dopamine D2 receptor antagonist, it blocks the pro-tumorigenic RAS-RAF-MEK-ERK pathway, achieving a 22% response rate in relapsed patients [137]. Dopamine receptors regulate nerve neoplasms, while neurotrophic factors BDNF and NGF drive tumor growth through Trk receptors. Trk inhibitors like larotrectinib and entrectinib are FDA-approved for solid tumors with NTRK gene fusions, regardless of tumor origin [138]. Acquired resistance remains a significant clinical problem, and next-generation inhibitors are being developed.

Preclinical evidence from mouse models suggests that neurotransmitter receptor agonists combined with anti-PD-L1 antibodies may synergistically modulate anti-tumor immune responses. Research on acetylcholine signaling revealed that CHRNA7 receptor activation promotes dendritic cell maturation and enhances CD8+ T-cell response, suppressing neoplasms in TNBC mouse models. The combination of CHRNA7 agonist with anti-PD-L1 antibody showed strong synergy, offering a strategy for “cold tumors” that respond poorly to immune checkpoint inhibitors [139]. Though these combinations have not yet entered human clinical trials, the findings highlight the potential of targeting nerve-immune interactions for anti-tumor immunity.

Cancer treatment via denervation or targeted nerve injury

Denervation studies have provided further evidence that the nervous system promotes the neoplastic progression. Zhao et al. demonstrated in three different mouse models of gastric carcinoma that surgical resection of the vagus nerve or local injection of botulinum toxin A (BoNT-A) significantly reduced tumor development [140]. Notably, optogenetic stimulation of the optic nerve can induce glioma formation, whereas sensory deprivation (such as dark rearing) inhibits tumor development [7]. These experiments, performed in mouse model, highlight the importance of neural activity in tumor initiation. Vats et al. demonstrated in mouse melanoma models that sensory nerves hinder the formation of tertiary lymphoid structures and protective anti-melanoma immune responses. Sensory denervation enhanced T-cell clonality and expanded the B-cell repertoire within the tumor microenvironment, suggesting that denervation can reshape the immune landscape to improve treatment outcomes [141].

However, there is an apparent contradiction between the emerging therapeutic strategy of tumor denervation and the long-established surgical principle of nerve preservation. In surgical oncology, nerve-sparing techniques have been standardized to preserve organ function and protect patient quality of life. For example, nerve-sparing radical trachelectomy in cervical cancer preserves pelvic nerves to maintain uterine function and fertility [142]. Similarly, higher rates of nerve preservation during radical prostatectomy improve postoperative erectile function and urinary continence [143]. Nerve-sparing retroperitoneal lymph node dissection in testicular cancer preserves ejaculatory function while achieving complete tumor resection [144].

How can these two seemingly contradictory approaches, denervation therapy versus surgical nerve preservation, both be valid? This requires consideration of several factors. Firstly, different types of nerves exert opposing effects on tumors. Sympathetic and sensory nerves generally promote tumor progression, while parasympathetic nerve function is more complex and depends on the tumor microenvironment [145]. Surgical nerve-sparing techniques primarily preserve autonomic nerves essential for organ function, whereas therapeutic denervation strategies target pro-tumorigenic nerve populations, such as sensory nerves [141]. These findings suggest that denervation can remodel the immune landscape to improve tumor treatment outcomes. Second, neural regulation of tumors varies by disease stage. While sympathetic nerves generally promote cancer progression, they may play protective roles during early tumorigenesis [34, 146]. Therefore, denervation strategies must be appropriately timed.

Third, denervation therapy shows different efficacy across tumor types. For brain tumors, non-specific denervation is rarely feasible. Due to the unique relationship between brain tumors and nervous system function, as well as the distinct characteristics of the neuronal subtypes involved, denervation therapy for brain tumors presents greater challenges. Disrupting pathological neuron-tumor synapses without affecting normal synapses presents significant challenges. The blood-brain barrier further complicates drug delivery and precise targeting of denervation strategies. For peripheral tumors, denervation shows greater promise. Ji et al. comprehensively reviewed tumor denervation strategies, from molecular mechanisms to innovative approaches including surgical denervation, pharmacological denervation (botulinum toxin, capsaicin), and targeted disruption of nerve-tumor crosstalk [147].

It is essential to clarify that the emerging concept of cancer-induced neural injury (CINI) is not intended to suggest any change to current standard-of-care surgical practices, nor does it imply that nerve-sparing resection should be avoided. On the contrary, surgical resection remains the cornerstone of curative treatment for solid tumors, and nerve preservation is critical for maintaining patient quality of life and preventing neurological deficits. What the CINI findings reveal is a biological mechanism underlying post-surgical tumor progression and therapy resistance—not a contraindication for surgery itself. During standard resection, particularly in anatomically complex regions such as the pancreas, head and neck, or near major nerve bundles, residual microscopic disease may be exposed to adjacent nerve structures. The CINI model suggests that these residual tumor cells, rather than the bulk resected tumor, can actively interact with and damage exposed nerve fibers. This provides a mechanistic explanation for why some patients experience aggressive recurrence despite successful gross tumor removal, and points to the potential need for adjuvant therapies targeting neural-tumor interaction pathways (e.g., IL-6 or type I interferon signaling) in the post-operative setting. We emphasize that there is currently no evidence to support altering standard surgical approaches based on these preclinical findings. Surgical resection with clear margins and, where appropriate, nerve preservation remains the standard of care. CINI research should be viewed as identifying a targetable mechanism that could complement, not replace, existing treatment paradigms.

All of the denervation studies described above were conducted in animal models (mice, rats). To date, no denervation strategy has been approved for cancer treatment in humans based on these mechanisms. Baruch et al. confirmed in preclinical models that tumor-associated neuronal injury is closely related to tumor resistance to PD-1 inhibitors. Targeting nerve injury/repair and inflammation-related molecules can reverse tumor resistance to immunotherapy [87]. A 2025 commentary in Neuron further emphasized that targeting tumor-associated nerves enhances cancer immunotherapy, highlighting the clinical potential of combining denervation with immune checkpoint blockade [148].

Although evidence from animal models is compelling, this remains a theoretical proposal awaiting clinical validation, further research is needed to translate these findings into human cancer therapies [2, 3, 149, 150]. Many nerve-targeted interventions exhibit only transient efficacy. Several factors likely contribute to this limitation. First, tumors may develop compensatory mechanisms to bypass denervation, such as upregulating alternative growth factor pathways or recruiting different nerve subtypes [2, 3]. Second, the tumor microenvironment is highly dynamic, and neural signaling patterns may evolve during disease progression and in response to therapy. Third, most preclinical studies evaluate efficacy over relatively short timeframes (typically 2–4 weeks in mouse models), which may not capture the emergence of resistance that would occur over months to years in human patients [149]. This limitation does not invalidate the potential of denervation strategies but rather argues for their integration into multimodal therapeutic approaches. Combining denervation with conventional chemotherapy, radiotherapy, or immunotherapy may produce more durable responses by simultaneously attacking tumors through multiple independent mechanisms [150].

Remodeling the immune system through neural modulation for cancer therapy

The immune system is also an important mediator of the interactions between the nervous system and neoplasms. Neural regulation within the tumor microenvironment can weaken immune surveillance and promote tumor immune evasion. Therefore, targeting neuro-immune crosstalk represents a promising strategy not only for controlling neoplasms but also for addressing tumor-induced nervous system complications.

Neurons can influence immune cells through multiple mechanisms. For example, MDK secretion can paradoxically activate CD8+ T cells, thereby promoting immune evasion [151]. In vitro studies by Liu et al. demonstrated that MDK inhibitors enhance the efficacy of immunomodulators in ovarian cancer cells [152]. Neurons also secrete TGF-β to stimulate CD4+ T cell proliferation and produce Fas ligands to induce T cell apoptosis. In basal-like breast carcinoma, low TGF-β activity is associated with enhanced CD4+ T-cell function and a reduced relapse rate, suggesting that inhibition of the TGF-β signaling pathway may improve immunotherapy outcomes. These data indicate that inhibition of the TGF-β pathway may represent a promising therapeutic strategy to enhance the efficacy of the immune system in treating basal-like breast carcinomas [153].

Recent study further elucidated that TSP1 secreted by glioma cells can promote synapse formation, leading to excessive excitation of neurons, which induces TAMs to polarize towards an anti-inflammatory M2 phenotype and suppresses the function of CD8+ T cells, thereby establishing a localized immunosuppressive microenvironment. Notably, the AMPA receptor antagonist perampanel, which targets this pathway and is an FDA-approved anti-epileptic drug, successfully reversed immunosuppression in preclinical models and extended mouse survival by 19.5%, demonstrating the potential of drug repurposing [154].

In addition, recent studies have revealed a new strategy for treating tumors by synergistically activating the STING and LTβR innate immune pathways, which not only directly suppress tumors through CD8+ T cells, but more importantly, induce the formation of functionally intact tertiary lymphoid structures (TLSs) within the tumor, thereby synergistically enhancing both anti-tumor humoral immunity (driving B cells to mature into plasma cells and memory cells) and cellular immunity (promoting T-cell recruitment and memory formation). It has demonstrated strong potential in neoadjuvant therapy settings to effectively prevent neoplasm recurrence and achieve long-term survival, thereby providing a new direction for improving the efficacy of cancer immunotherapy [155]. A recent study by Shuqi Cai et al. provides direct evidence that chemotherapy-induced neural remodeling leads to the formation and maturation of TLSs, a hallmark of local anti-tumor immune activation [156]. Notably, nerve-proximal TLSs (N-TLSs) displayed more mature phenotypes and correlated positively with tumor regression. These findings indicate a spatially organized neuro-immune axis linking neural remodeling to TLS abundance and maturation after chemotherapy, and nominate N-TLS abundance as a potential histological biomarker of treatment response in resected PDAC [156].

Although immunotherapy has revolutionized cancer treatment, its efficacy remains variable, requiring further improvement and the development of new immunotherapies specifically designed to disrupt neuro-neoplasm immune pathways. At the technical level, significant innovations have emerged worldwide in 2025. For instance, one research designed novel nanoparticles through local postoperative administration into the surgical cavity and precise disruption of mitochondrial function in tumor cells, successfully activated the cGAS-STING innate immune pathway, recruited cytotoxic T cells, and remodeled the immunosuppressive microenvironment, effectively preventing relapse in GBM models [157, 158]. Another approach employs engineered bacterial outer membrane vesicles (OMVs) conjugated with a nerve‑targeting peptide and loaded with a tropomyosin receptor kinase (Trk) inhibitor. These vesicles selectively interfere with neurotrophin/Trk signaling, inhibit neurite outgrowth, and repolarize tumor‑associated macrophages toward an M1 phenotype, collectively suppressing nerve‑driven pancreatic cancer progression. Such innovative delivery platforms highlight the potential of precisely targeting the neural component of the tumor microenvironment to enhance therapeutic outcomes [159].

Moreover, another research published in April 2025 has identified AI-driven target discovery and solid tumor CAR-T therapy as key research priorities, laying the foundation for future breakthroughs in neuro-immunotherapy.

Conclusion and perspectives

Conclusion

The theoretical framework of tumor neuroscience has evolved from a linear “nerve-tumor” bidirectional conversation to “nerve-immune-tumor” tripartite interaction. Advances in the realm of cancer neuroscience mark a fundamental shift in cancer biology research paradigms [2, 3]. Recent studies have established the core role of the nervous system in actively regulating malignant tumor progression through multidimensional mechanisms. The mechanisms encompass direct synaptic connections, such as the functional glutamatergic synapses identified in gliomas, and the sensory nerve-cancer cell “glutamatergic pseudo-synapses” observed in pancreatic ductal adenocarcinoma, the latter facilitating tumor invasion [154, 160]. Additionally, the transmission of neurotransmitters and neuropeptides, including substance P, regulates tumor cell proliferation and metastasis through their respective receptors [26, 67, 94]. Furthermore, the newly recognized concept of CINI reveals that chronic neuroinflammation resulting from nerve myelin destruction drives both immunosuppression and resistance to immune checkpoint inhibitors, demonstrated that neurons functions as systemic immune microenvironment remodeling [85, 87]. Lastly, unprecedented energy metabolism support is evidenced by a study confirming that neurons can directly transfer their mitochondria to breast cancer cells via tunneling nanotubes, significantly enhancing the latter’s metabolic plasticity and metastatic colonization capability [84]. This finding suggests that nerve-cancer interaction is more than just signal transmission, it is also energy supply.

Limitations and open questions

These discoveries collectively construct the theoretical framework of the complex “neuro-tumor- immune” regulatory networking. Despite breakthroughs in mechanistic studies, this field still faces severe challenges at the foundation and translational levels [2, 3, 149]. Key scientific questions should be addressed. Several emerging findings, such as the transfer of neuronal mitochondria to cancer cells, tumor-suppressive neural circuits underlying social behaviors, and stage-specific switching of sympathetic nerve function, still require rigorous validation in more preclinical models and clinical samples. How does this mechanism relate to previously identified neurotransmitter signaling and synaptic connections? What are the molecular mechanisms that govern the functional switch of sympathetic nerves from protective in early tumorigenesis to pro-tumorigenic in established cancer?

Second, the stage-specific functional switching of nerves is poorly understood. For example, sympathetic nerves appear to be protective during early tumorigenesis but become pro-tumorigenic in established cancers. The molecular mechanisms governing this switch remain elusive. Key questions include: What roles do factors such as Netrin-1, changes in adrenergic receptor expression, and evolution of the immune microenvironment play in this transition? Understanding this transition is essential for determining the optimal timing of neural-targeted interventions [35]. Patient selection based on disease stage and molecular biomarkers of neuro-tumor crosstalk will be critical for successful clinical translation.

Thirdly, the spatiotemporal dynamics of the neuro-immune-tumor interaction network during tumor progression are completely unknown. How do neural signals crosstalk with other stromal cells in the tumor microenvironment, such as pericytes and endothelial cells? Does the relative contribution of direct synapses vs. paracrine signaling change as tumors evolve from initiation to metastasis? Current studies are almost exclusively static snapshots, and longitudinal in vivo imaging of these interactions remains a major technical hurdle.

Fourth, causality versus correlation remains a central issue. The majority of evidence linking neural density or activity to tumor progression is correlative. While optogenetic and chemogenetic tools have established causality in mouse models, functional validation in human cancers is scarce. It is unclear whether the structural and functional changes observed in tumor-innervating neurons are true drivers of progression or merely epiphenomena of a complex and inflamed tumor microenvironment.

Fifth, we lack tools to specifically target tumor-associated nerves without impairing normal physiological neural function. Current interventions—such as surgical denervation, chemical ablation, or broad-spectrum neurotransmitter receptor blockers—are non-selective and often cause significant side effects. Developing strategies that discriminate between “pathological” neural circuits that support cancer and “physiological” circuits that maintain normal organ function is a major translational bottleneck.

Sixth, human-relevant models are underdeveloped. Most discoveries rely on murine systems, and findings often fail to translate to humans due to species differences in neural anatomy, immune systems, and tumor biology. Organoid and co-assembloid models that preserve innervation are still in early stages, and intraoperative or fresh human tissue validation is rare. Furthermore, there are no established non-invasive imaging biomarkers to monitor neuron-tumor network activity in patients, severely limiting clinical trial design.

Finally, the field has disproportionately focused on immunosuppressive neural effects, largely ignoring the possibility that specific neural circuits, neurotransmitters, or hormones might exert immunostimulatory effects. Whether such protective neural circuits exist in the peripheral nervous system, and whether they can be therapeutically augmented, remains an open and exciting question.

Clinical attempts and future directions

Ongoing research directions

Several lines of investigation are actively ongoing to address the current limitations. Researchers are systematically delineating the specific neuronal subtypes (e.g., glutamatergic, GABAergic, adrenergic, sensory) that interact with different cancers, using optogenetic and chemogenetic tools in murine models to establish causality. There is a major push to characterize the molecular architecture of neuron-cancer synapses via single-cell transcriptomics and to identify the cancer-intrinsic “neuronal gene clusters” required for synapse formation. Organoid and tumoroid models are being refined to bridge the gap between animal studies and human tissue. In neuro-immuno-oncology, efforts focus on mapping how distinct neuronal populations modulate specific immune cells (T cells, NK cells, macrophages, MDSCs) in an entity- and location-specific manner. The role of CAFs in neural remodeling and perineural invasion is another active area. Technologically, researchers are developing advanced in vivo tracing methods (e.g., modified rabies virus, tissue clearing, 3D imaging) to map the full connectome from tumor to neuronal soma. Intravital imaging and improved electrophysiological preparations (patch-clamp) are being adapted for extracranial tumors. Furthermore, studies are beginning to investigate tumor-induced changes in neuronal structure and function, asking whether these changes are a cause or consequence of progression. Finally, the impact of cancer on CNS neurons and glial cells—astrocytes and microglia—is receiving increasing attention, though this remains an under-researched area.

Clinical translation challenges

Several clinical translational attempts have encountered setbacks. For instance, non-specific neurectomy is limited by severe adverse effects. Direct intervention strategies like denervation face a steep road to clinical application due to four key challenges. Lack of targeting precision can damage healthy nerves, while long-term safety is still unknown. Additionally, differences between tumor types make it hard to reproduce treatment effects consistently. Most importantly, the tumor immune microenvironment is so complex that we cannot easily predict or control how it will react to neural interventions. These issues together prevent these promising strategies from being used more widely in the clinic.

At the translational application level, the biggest bottleneck lies in the specificity and safety of intervention strategies. Precise targeting of tumor-associated nerve signals without affecting the physiological functionality of healthy nerves is a core challenge for drug development. Furthermore, when targeting nerve interactions in brain tumors, the blood-brain barrier greatly limits the effective delivery of therapeutic drugs, which calls for innovation in novel drug delivery systems. When future research is translated to clinical applications, it not only needs to resolve the precise functionality of different nerve subtypes in specific tumor microenvironments but also faces the challenge of how to precisely intervene without disrupting healthy nerve functionality. With the development of disciplines, intervention strategies targeting this network, that is, “neural checkpoint modulation” are expected to open up new avenues for cancer treatment.

Future research directions

The future of cancer neuroscience hinges on a systematic, multi-pronged approach. First, we need cancer-type-, site-, and stage-specific mapping of the “neuro-cancer connectome” to understand why neural signals can have variable or even opposite effects (e.g., growth-promoting in glioblastoma vs. differentiation-inducing in ependymoma). Spatial transcriptomics and single-cell sequencing can be utilized to map this neuro-tumor interaction cell atlas. Second, researchers must establish causal, mechanistic links using advanced tools: circuit-specific opto/chemogenetics in autochthonous mouse models, combined with longitudinal intravital imaging, to dissect whether structural neuronal changes drive progression. Third, a major effort should be made to validate findings in human tissue using intraoperative imaging, freshly resected samples, and human organoid/co-assembloid models that preserve innervation. Fourth, the field must comprehensively map the neuro-immune-oncology axis by correlating neural and immune profiles from patient samples and then interrogating these correlations in well-controlled mouse models, paying equal attention to immunostimulatory possibilities. Fifth, in-depth exploration of novel communication patterns is required, such as organelle transfer (e.g., neuronal mitochondria transfer to cancer cells), by which the nervous system regulates peripheral tumors. Sixth, technological development is paramount: we need better viral tracers for long-distance circuit mapping, standardized patch-clamp preparations for various tumor types, and non-invasive imaging biomarkers for human use. Seventh, future research should expand beyond neurons to include glia and other stromal cells, and should investigate the metastatic cascade and the role of circadian and stress pathways. Eighth, a community-wide effort to establish standardized, peer-reviewed protocols and shared connectome data resources will lower entry barriers and accelerate discovery.

Translational roadmap

The focus of translational research will be on three major areas. First, developing neuro-targeted drugs with high specificity, including repurposed agents such as β-blockers and CGRP antagonists, as well as novel small molecules targeting neural checkpoint modulators. Second, constructing intelligent drug delivery systems to break through the blood-brain barrier, enabling effective treatment of brain tumors and brain metastases. Third, designing systematic treatment schemes that integrate neural interventions with existing therapies.

The most promising strategy is the combination of denervation (or neural signal blockade) with immune activation, in order to synergistically disintegrate the tumor-supportive neural network. This combinatorial approach aims to overcome tumor therapy resistance and metastasis, enabling comprehensive prevention and treatment patterns. Ultimately, these efforts will lead to a new pillar of oncology: neuroscience-instructed cancer therapies (NiCTs), which target specific nodes in neural-tumor networks with repurposed drugs or novel interventions. The next decade will likely see the first clinical trials testing such combination strategies, aiming to improve both disease control and quality of life.

Author contributions

XM.L.: Writing – original draft, YX.L.: Writing – original draft, figures drawing: XY.S.: Writing – original draft, review & editing, YY.W.: Conceptualization, Writing – original draft, review & editing, Visualization, Formal analysis, Funding acquisition, SP.J.: review & editing, Supervision, Funding acquisition, Project administration. All authors reviewed the manuscript

Funding

This work was supported by grants from National Natural Science Foundation of China (NSFC) (No.31371386. SP. J., No.30871239. SP. J. No.32200804，YY.W.); Foundation of He’nan Educational Committee (NO.23A310016) and program for Science and Technology Development in Henan Province (NO.242102311048).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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Not applicable.

Competing interests

The authors declare no competing interests.