The influence of neuro-tumor interactions on tumorigenesis and therapeutic response.

Introduction

The nervous system is a sophisticated network integrated by nerves and cells that facilitates the communication between various parts of the body. It can be broadly categorized into two main components: central nervous system (CNS) and peripheral nervous system (PNS). Traditionally, the primary function of nervous system is to regulate the bodily activities by transmitting information, enabling the body to adapt to environmental changes and maintain homeostasis [ 1 ]. Interestingly, in certain instances, neural activity plays a significant role in regulating various pathological functions, and has a profound impact on disease progression, particularly in cancers [ 2 ].

The past half decade has seen the emergence of bidirectional nerve-tumor interplay, a phenomenon that has been documented in aggressive malignancies such as brain tumors [ 3 , 4 ], colorectal cancer (CRC) [ 5 ], breast cancer (BC) [ 6 ], etc. This interaction is frequently linked to the secretion of neurotrophic factors within the tumor microenvironment (TME), which promotes the infiltration and growth of nerves into tumor stroma. In turn, these nerves can secret growth factors, neurotransmitters and other signal molecules within TME, consequently stimulating the growth of cancer cells and enhancing the activity of tumor-supporting cells [ 7 , 8 ]. Moreover, increasing evidence has identified numerous direct neuron-tumor interactions, paracrine signaling within TME, and indirect crosstalk between the nervous and immune systems [ 9 , 10 ]. Although it has been demonstrated that blocking neuroregulatory signals can have a regulatory effect on tumors, the detailed mechanisms by which nerves regulate tumor progression are still not fully understood. Ongoing research is progressively elucidating the molecular pathways and biological functions that nerves play in tumor behaviors.

In this review, we outline recent key investigations into the complex crosstalk between cancer, neurons and body [ 11 ], including the emerging interdisciplinary subfields cancer-immune system-neuron interface [ 12 ]. We have assessed the key mechanisms underlying nerve-tumor interactions, including specific neural components and signaling pathways, highlighting their collective contribution to cancer biology, including cell proliferation, metastasis, immune remodeling, and angiogenesis. Additionally, this review identifies several unresolved issues in this fast-growing field, and provides the possible solutions to address these certain challenges. Finally, we discuss the potential benefits of targeting nervous system in cancer treatment, with an emphasis on repurposing existing neurological drugs for oncological applications.

The roles of nerves on cancer biology

Over the past several years, the emerging topic of “Cancer Neuroscience” has significantly illuminated the crucial roles played by the neuronal biology in cancer. Tumor-infiltrating nerves were initially reported in 1897 [ 13 ]. However, it was not until the dawn of the twenty-first century, spurred by advancements in imaging techniques, that in-depth scientific exploration of their functions began to gather pace. This progression culminated in the formal recognition of cancer neuroscience as an independent field in 2020 [ 14 ]. A multitude of research efforts have underscored the vital connections between intratumor nerves and cancer cells (Fig. 1 ; Table 1 ). More recently, attention has turned to the intricate relationships these nerves have with diverse elements of TME [ 15 ]. Specifically, the nervous system displays a significant impact on cancer progression through the secretion of neurotransmitters, like norepinephrine. These neurotransmitters can directly bind to the specific receptors on cancer cells, and then change the activation of downstream signals [ 16 ]. Additionally, nerve fibers can indirectly regulate anti-cancer immunity by interacting with immune cells. For instance, in BC tissues, the parasympathetic nervous system is capable of facilitating the tumor recruitment of cytotoxic T lymphocytes (CTLs) and suppress the polarization of M2-like macrophages, consequentially improving anti-cancer immune response [ 17 ]. Therefore, neuro-tumor crosstalk is modulated by an intricate molecular network encompassing neurotransmitters, neurotrophic factors, and immune checkpoints. This complex intercellular communication not only drives tumor cell proliferation, invasion, and angiogenesis but also reshapes the TME, consequentially interfering the therapeutic efficacy [ 18 , 19 ].

The stimulating effect of neuronal activity on cancer growth

The influence of nervous system on tumorigenesis has been increasingly drawing attention. Multiple investigations have revealed the presence of neuron-like structures within tumor tissues. Moreover, the density of nerve fibers has a correlation with the extent of tumor progression. Current reports have indicated that tumor cells might display neuro-oncological addiction [ 20 , 21 ], with several independent research groups presenting crucial clues for the neural regulation of glioblastoma (GBM) [ 22 – 24 ].

It was hypothesized that glioma cells exert the proliferative potential in response to neuronal activity [ 25 ]. Reciprocally, glioma cells interact with the neuronal environment, underlining the clinical relevance of functional network connectivity for tumor growth [ 26 ]. For example, sialic acid assumes a vital role in maintaining functional connectivity and cell excitability within neuronal networks [ 27 ]. The accumulation of sialic acid on cell surface serves as a driving factor for the cell-to-cell connectivity of GBM cells and the formation of GBM-neuro networks. This phenomenon mainly occurs by decreasing calcium spiking, which in turn contributes to the pathology of GBM [ 28 ]. Thus, the establishment of connectivity within the neuron-tumor network plays a stimulating role for the proliferation and invasion capabilities of tumor cells. Translational researches based on brain mapping, a proxy technology for monitoring the brain neuronal networks [ 29 ], have proven that elevated levels of neuronal activity not only in the area surrounding the tumor but also throughout the hemisphere where the tumor is located [ 26 , 30 ]. The glucocorticoid receptor (GR), an evolutionarily conserved nuclear receptor [ 31 ], possesses the capacity to mediate bidirectional crosstalk between tumors and nervous system. Glucocorticoids (GCs), the GR’s primary ligands, are predominantly secreted by the hypothalamic-pituitary-adrenal (HPA) axis in response to stress [ 32 – 35 ]. GCs, such as dexamethasone (DEX), have been found to directly foster the growth of GBM through activating GR signaling pathway [ 36 ]. In vivo and in vitro analysis uncover a positive correlation: higher GR levels associate with increased disease risk among patients [ 37 ]. Additionally, GR directly modulates the expression of neurotrophic factors (e.g., brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) in sensory neurons [ 38 ], which act on tumor cells to amplify neuro-tumor crosstalk. Recent research has yielded ample evidence regarding the complex reciprocal crosstalk between gliomas and neurons in the TME. this neuron-GBM interaction has been shown to synchronize the circadian rhythms in tumor cells by activating GR signaling, in turn significantly accelerating the disease progression [ 39 ]. Through integrating intraoperative electrocorticography recordings and human single-cell RNA-sequencing (scRNA-seq) results, Curry’s group [ 40 ] identified unique molecular signatures of synaptic remodeling as characteristic features of tumors in patients with glioma-related epilepsy. Meanwhile, this group identified immunoglobulin superfamily member 3 (IGSF3), a gene participating in synaptic formation, as a novel regulatory factor for both tumor proliferation and neural circuitry dysfunction. IGSF3 drives potassium dyshomeostasis to aggravate seizure burden through interacting with the inwardly rectifying potassium channel Kir4.1, sequentially contributing to brain hyperactivity and gliomagenesis driven by epilepsy. A specific network-unconnected subpopulation of GBM cells has been recently found to present the neural progenitor-like features. During neuronal development, these subpopulations could receive the neuronal synaptic input signal, which enables them to invade into new areas of brain [ 41 ]. Intriguingly, these metastatic subpopulations have a particularly proliferative capacity in all infiltrated brain regions [ 42 ], indicating the interrelation between invasion and proliferation during gliomagenesis.

Similar to the findings in the GBM models discussed above, the regulation of neuronal mechanisms in promoting cell growth has also been confirmed in other cancers. For example, the distribution profiles of neurons and their relevance with patients’ clinicopathological characteristics have been recently assessed in CRC tissues. The levels of two neurogenetic biomarkers, protein gene product 9.5 (PGP9.5) and neurofilament (NF), were notably increased in the tumor stroma. The patients possessing NF/PGP9.5-positive nerve fibers displayed unfavorite prognostic outcomes [ 43 ].

Generally, sympathetic and parasympathetic nervous systems, two major components of autonomic nerves, exhibit antagonistic functions during the physiological processes. However, in poorly-differentiated and high-grade cancers, these two types of nerves are interconnected and have been shown to synergistically promote tumor growth and progression [ 44 , 45 ]. The neurotrophins secreted from autonomic nerves, including NGF and brain-derived neurotrophic factor (BDNF), also participate in cancer cell growth and metastasis [ 46 ]. Moreover, aberrant sympathetic and parasympathetic signals could further promote the infiltration of myeloid-derived suppressor cells (MDSCs) into TME. This recruitment gives rise to the formation of an immunosuppressive microenvironment, which in turn facilitates the aberrant proliferation and differentiation of cancer cells [ 47 ]. Accordingly, in salivary duct carcinoma (SDC), a type of highly malignant tumor, Kajiwara’s group discovered S100-positive nerves in 72.9% (94 out of 129 cases) of the cancer tissues. Among them, there are 92 cases with tyrosine hydroxylase (TH)-positive sympathetic nerves, and 59 cases showed the co-expression of TH-positive sympathetic nerves and vesicular acetylcholine transporter (VAChT)-positive parasympathetic nerves. The existence of autonomic nerves is negatively linked to histological characteristics and survival time [ 48 ].

In addition, the presence of neural progenitor cells (NPCs) within TME is also associated with unfavorable clinical and histological characteristics [ 49 ]. The research performed by Mauffrey and colleagues [ 50 ] has proven that recruitment of doublecortin (DCX)-positive NPCs into tumor tissues may control the early development and progression of prostate cancer (PC). Single-cell spatial analysis of neural elements indicated that existence of DCX + neural progenitors within BC stroma is linked to the malignant phenotypes, characterized by poor differentiation, higher proliferation ability, and lymph node (LN) metastasis [ 51 ]. Therefore, the detection of neuronal profiles is of great significance in predicting the growing status of cancer patients [ 52 , 53 ].

Neuronal activity in cancer metastatic process

It is well-established that nervous system can augment the invasive capabilities of cancer cells through interacting with them, and enable both lymphatic and vascular dissemination [ 54 ] (Fig. 2 ). For instance, the peripheral fibers from autonomic nervous system exert a positive impact on all metastatic tumor growth in visceral organs [ 55 ]. Neuronal activity can favor the colonization of metastatic cancer cells into important organs, including brain [ 56 ]. In pancreatic ductal adenocarcinoma (PDAC), tumor cells have the ability to migrate along nerve fibers to reach the extratumoral areas, contributing to recurrence [ 57 ]. Notably, an increase of circulated placental growth factor (PIGF) has been observed to promote directional and dynamic alterations in the plasticity of neurites from dorsal-root-ganglia neurons. This occurs when these neurons are exposed to guidance and growth factor signals originating from PDAC. Meanwhile, PlGF plays a functional role in facilitating the reciprocal chemoattraction between cancer cells, neurons, and neuroglial cells (e.g., Schwann cells), synergistically driving the neurogenesis and neural invasion [ 58 ]. A combination treatment with anti-PlGF and chemotherapy potentiated growth and metastasis inhibition of PDAC cells [ 59 ]. In addition, overexpression of paracrine sonic hedgehog (SHH) in pancreatic cancer cell significantly upregulating the hedgehog signaling of stromal cells, subsequentially facilitating nerve outgrowth with TME and cell migration along nerve fibers [ 60 ].

In malignancies, perineural invasion (PNI) is closely related to neural involvement-mediated local and distant metastasis, playing a distinct role in the processes of tumor spread and progression [ 61 ]. PNI is defined as the presence of cancer cells in the perineurium, which occurs when tumor cells infiltrate the perineural space and then spread along the nerves to distant sites [ 62 ]. The mutual interaction between nerves and other cells (cancer cell, Schwann cells and immune cells) propels PNI, which is regulated by multiple molecules, such as secreted neurotrophins [ 63 ]. In BC, the acquisition of neuro-adaptive characteristics enabled by elevated serine/arginine repetitive matrix protein 4 (SRRM4), a splicing factor specific to neurons, could dramatically prompt the CNS metastasis of BC cells [ 64 ], supporting that high nerve density result in high metastatic potential [ 65 , 66 ]. PNI is often observed in BC tissues with higher activity of α-smooth muscle actin (α-SMA), an important compound of extracellular matrix (ECM). Stiff matrix, the ECM with relatively high degree of hardness, triggers activation of focal adhesion kinase (FAK)-yes-associated protein (YAP) signal axis and upregulation of neurotrophic genes (NGF, BDNF, neurotrophin 3 (NTF3), and neurotrophin 4 (NTF4)) through binding to its functional receptor integrin β1. These processes not only enhance the invasiveness of cancer cells but also promote the neurotrophy-associated PNI effects [ 67 ].

The infiltration of nerve fibers into microenvironment is a feature during tumor metastasis. The BC patients who had elevated levels of neuropeptide substance P (SP) show the increased capacity of lymph node metastases. BC cells could dramatically trigger the spontaneous calcium activity and SP release from sensory neurons. After then, SP exerts its stimulating effect on tachykinin receptors (TACR1), which in turn drive the death of cancer cells. The single-stranded RNAs (ssRNAs) derived from dying cells could activate toll-like receptor 7 (TLR7) in adjacent cell, thereby enabling the pro-metastatic gene signature in BC cells [ 68 ].

Neurons system for blocking cancer progression

The interplay between nervous system and tumor development is elaborate, involving diverse and interwoven processes. Under certain circumstances, neuronal activity can exhibit anti-tumor properties, particularly in highly aggressive cancers like BC and melanoma. Semaphorins (SEMA) and their receptor neuropilins are originally identified as axon-guidance molecules during nervous system ontogenesis [ 69 ]. Vascular endothelial growth factor (VEGF)-A, a factor that drives BC cell migration, specifically binds to the neuropilins within TME. High levels of SEMA3B can competitively bind to neuropilins more effectively than vascular endothelial growth factor A (VEGF-A), thereby impeding cancer cell migration and proliferation [ 17 , 70 ]. In KC (LSL: Kras G12D: Pdx1-Cre) mouse models, subdiaphragmatic vagotomy or cholinergic receptor muscarinic 1 (CHRM1) knockout significantly promotes the progression of PDAC. Treatment with the CHRM1 agonist bethanechol mitigates vagotomy-induced tumor incidence by directly inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK)/epidermal growth factor receptor (EGFR) signaling pathways within cancer cells, or indirectly suppresses myeloid cells [ 71 ].

In addition, activation of sensory neurons can effectively impede melanoma growth and angiogenesis. This anti-tumor effect is characterized by enhanced recruitment of anti-tumor immune cells (e.g., natural killer (NK) cells, CD4 + helper T cells, CD8 + cytotoxic T cells and γδ T cells), and concomitant reduction in immunosuppressive cell populations (e.g., MDSCs and neutrophils). Furthermore, sensory stimulation has been found to promote the accumulation of tumor-infiltrating lymphocytes that secrete interleukin-17 (IL-17), a cytokine with anti-tumorigenic potential [ 72 ]. Similarly, activated sensory nerve fibers enhance the infiltration of CTLs and boost the interferon-γ (IFN-γ) response, subsequentially resulting in the inhibition of BC metastasis [ 73 ].

Furthermore, it is widely believed that controlling the release of peptides by nervous system is pivotal in cancer progression. Through mimicking the inflammatory neural circuitry, vagal nerve stimulation triggers an increase in trefoil factor 2 (TFF2), a peptide secreted by memory T cells, and then suppresses the proliferation of MDSCs and prevents colorectal carcinogenesis (CRC). Conversely, splenic denervation disrupts the anti-inflammatory neural pathway, allowing MDSCs to proliferate and contributing to CRC development [ 74 ].

Neuro-tumor crosstalk

In neuro-oncology, it is widely believed that a profound interaction exists between nervous system and malignancies. Moreover, the neuro-tumor crosstalk is characterized by remarkable complexity [ 75 , 76 ]. The nervous system has been proved to contribution to tumor development and progression. Conversely, tumors also exhibit diverse neural characteristics, enable them to actively reshape the structure and function of nervous system [ 77 , 78 ] (Table 2 ; Fig. 3 ). For example, extracellular vesicles (EVs) secreted by multiple cancer cell types [ 79 – 84 ], like cervical cancer (CC) [ 85 ] and head and neck squamous cell carcinoma (HNSCC) [ 86 , 87 ], could function as the attractants, prompting the migration of nerve fibers towards tumor site and significantly stimulating the outgrowth of tumor-infiltrating nerves. Elevated nerve density has been found in oral cancer tissues harboring p53 mutations. The inactivation of tumor protein 53 (TP53) in cancer cells initiates a cascade where the downregulation of miR-34a drives adrenergic trans-differentiation of tumor-associated sensory nerves. This neural reprogramming creates a supportive microenvironment for tumor progression, highlighting the critical roles of tumor-associated neuritogenesis in disease progression [ 88 ]. Notably, experimental interventions such as sensory nerve denervation or pharmacologically blocking adrenergic receptors have been shown to impede tumor growth [ 89 ]. GBM cells possess the remarkable ability to swiftly assimilate into neural circuits throughout the brain, establishing extensive communication channels between neurons and glioma cells. Intriguingly, radiotherapy, rather than suppressing this interaction, inadvertently fortifies neuron-tumor connectivity by boosting neuronal activity. The strategies that inhibit neuronal activity, when combined with radiotherapy, have demonstrated enhanced therapeutic sensitivity [ 90 ].

Tumor-derived signals represent a new homeostatic challenge for the neurological and cognitive function, as they can disrupt the normal physiological processes and lead to various neurological syndromes [ 91 ] and cognitive impairments [ 92 ]. The patients with advanced cancers frequently suffer from nerve damage and neurocognitive problems, which in turn leads to or exacerbates social withdrawal [ 93 ]. Accordingly, Henneghan & colleagues demonstrated the increased risk of cancer-related cognitive impairment (CRCI) during the course of cancer and its treatment, including trouble concentrating, memory deterioration, etc. These cognitive deficits not only have a detrimental impact on patients’ quality of life and survival prospects but also impede their social and professional activities [ 94 ]. By incorporating quality-of-life (QoL) parameters (mobility, sleep quality, social interaction ability, and cognitive status), Digital Phenotypic Assessment in Neuro-Oncology (DANO) indicates a potential long-term reduction in the social interaction capacity of individuals with brain tumors [ 95 ]. After then, the neuroendocrine consequences of social isolation increase in susceptibility to pulmonary metastases of BC cells in MADB106-bearing rats [ 96 ]. Therefore, the effective suppression of tumor growth, coupled with the mitigation of neurological risks, can lead to a substantial enhancement in the clinical outcomes for tumor patients [ 97 , 98 ].

Even though neuro-oncological regulation is still in its infancy [ 99 ], characterizing its regulatory patterns and functional outcomes will help clarify the contribution of innervation to cancer development and spread. This clarification holds the potential to discover new neuro-associated therapeutic targets in cancer management.

Neuro-immune axis in cancer

There is an increasing amount of evidence highlighting the crucial role of neuro-immune axis in cancer pathology [ 100 , 101 ] (Fig. 4 ). The existence of neural elements in TME, alongside the manifestation of tumor-associated antigens capable of triggering immune responses (Table 3 ), indicates that strong neuro-immune crosstalk might have important impacts on the progression of cancer [ 102 , 103 ]. In high-grade BC patients, high serum levels HLA-G displays positive correlation with sympathetic nervous system index, and negative correlation with parasympathetic parameters [ 104 ]. Moreover, the biomarker of serotonergic and dopaminergic neurons, rather than those of cholinergic neurons, exhibited a negative correlation with the activation of CD8 + T cells in papillary thyroid cancer (TC) [ 105 ]. During tumorigenesis, transforming growth factor-β (TGF-β) secreted by cancer cells stimulates Schwann cells to release prostaglandin E, which in turn inhibits CD3 + CD28 + T cell activation and upregulates programmed cell death protein 1 (PD-1) on T cells [ 106 ]. In addition, Neuro-immune cell interactions is also capable of altering the tumor-associated immunological landscape through recruiting immune cells, regulating multiple signaling pathways and releasing neurotransmitters/neuropeptides, all of which could support the tumor pathogenesis [ 107 , 108 ]. Intervening in the neuro-immune axis has the potential to significantly alter the immune phenotypes of cancers as well as overall survival time [ 109 , 110 ]. Transient receptor potential vanilloid-1 (TRPV1) is frequently expressed in both neuronal and numerous non-neuronal cells, including immune cells. Through regulation of neuro-immune microenvironment, TRPV1 contributes to the enhancement of anti-cancer immune response by releasing neuropeptides (e.g., calcitonin gene-related peptide (CGRP) and SP) and inhibiting chronic inflammation [ 111 ]. Interestingly, the equilibrium of neuroinflammation in axon regeneration and tumor growth is a crucial aspect to consider when treating optic pathway glioma. It has been reported that neuroinflammation can facilitate the axonogenesis and neuronal restoration during human diseases, with chemokine (C-C motif) ligand 5 (CCL5) being regarded as a vital factor [ 112 , 113 ]. At the same time, the secretion of CCL chemokine by nervous system serves as a key promoter for the growth of malignancies [ 114 ]. Blockade of CCL2/CCR2 axis by activated sympathetic nervous system expectedly enables the CD8 + T cell-dependent control of liver cancer [ 73 ].

In certain tumors, PNI-related cholinergic signaling can block the secretion of immunostimulatory cytokines such as IFN-γ. This blockage restricts the functionality of NK cells and cytotoxic T cells, thereby promoting tumor cell proliferation [ 115 ]. Within TME, the interactive behaviors between nociceptor neurons and cancer-associated fibroblasts (CAFs) are dependent on the nociceptor neurons-secreted CGRP, resulting in the downregulation of IL-15 in CAFs. These procedures expectedly intercept the infiltration and activity of NK cells, and then drive the development and progression of PDAC [ 116 ]. The findings from Erin’s group [ 117 ] demonstrated that sensory nerve fibers activated by olvanil significantly promote intratumoral infiltration of CD8 + T cells and augment IFN-γ response, subsequentially leading to the suppression of BC metastasis.

Functionally, neuro-tumor interactions could lead to remodeling of anti-tumor immune response-highlighting the potential of targeting neuro-immune molecules to improve therapeutic outcomes. The nervous system regulates anti-cancer immunity, highlighting a specific strategy for cancer treatment [ 118 ]. In mouse 4T1 breast tumor models, stimulation of sciatic nerve can effectively activate D1-like dopamine receptor-cAMP-PKA-cAMP-response element binding protein (CREB) signaling axis, which is crucial for augmenting the cytotoxicity of NK cells and inhibiting tumor growth. Meanwhile, neurostimulation elevates the expression of PD-L1 through elevating serum IFN-γ production, rendering BC cells more sensitive to immunotherapy [ 119 ]. In poorly-differentiated BC, treatment with neuronal SP dramatically improves the therapeutic sensitivity of radiotherapy by boosting the anti-tumoral immunity, charactered with decreased MDSCs, increased CD4 + CD25 bright cells and upregulated IFN-γ concentration within TME [ 120 ]. The neurotransmitter CGRP, secreted by medullary TC cells, disturbs the dendritic cells (DC) development by enhancing the generation of intracellular cAMP and impeding the loss of kruppel like factor 2 (KLF2), ultimately resulting in an immunosuppressive microenvironment with impaired tumor-infiltrating T cells. The CGRP receptor antagonist rimegepant can remarkably counteract the adverse effect of CGRP on DC development, consequently boosting the anti-tumor immunity of CD8 + T cells against thyroid cancer [ 121 ]. In brief, elucidating the fundamental functions of neuro-immune circuits in the tumor milieu will open up new avenues for identifying promising targets for innovative anti-cancer therapeutic strategies [ 122 ].

Despite extensive research on the crosstalk between neural and immune systems, significant knowledge gaps persist regarding how nerve fibers directly or indirectly regulate immune cell function and anti-cancer responses. Current understanding of the neuro-immune axis lacks detailed characterization of the signaling pathways and cellular interactions that govern anti-tumor immunity, highlighting the need for further investigation into this complex regulatory network.

Neuronal modulation of cancer angiogenesis

Angiogenesis, which refers to the development of new blood vessels inside tumors, is crucial for providing nutrients and oxygen to the expanding tumor mass [ 123 ]. It has been proven that blocking this process is an effective approach to curbing tumor growth and preventing metastasis [ 124 – 127 ]. Notably, emerging studies have uncovered that neuronal activity can regulate tumor angiogenesis [ 128 , 129 ], mainly via pro-angiogenic signaling in TME [ 130 ]. Neurogenesis and angiogenesis represent the intertwined biological processes that frequently manifest as characteristic features in human diseases [ 131 ], including cancers [ 15 ]. Wik and colleagues [ 132 ] conducted an in-depth analysis of the protein and mRNA profiles within BC cohorts. Through this comprehensive assessment, they successfully identified a well-established neuro-angiogenic signature that was linked to malignant progression and reduced survival. More importantly, anatomical studies revealed a notable co-localization of neural and vascular components within tumor areas.

The axon-guidance molecules, neuropilins, have been proved to be important pro-angiogenic factors and play a pivotal role in facilitating VEGF-A-mediated enhancement of sensory neuron excitability and tumor growth. Disrupting of VEGF-A-neuropilin-1 (NRP-1) interaction could effectively mitigate the VEGF-A-induced hyperexcitability of dorsal root ganglion (DRG) neurons [ 133 ]. Meanwhile, the findings from Michaelsen’s group proposed that the antagonistic effect of VEGF antibody bevacizumab on tumors might dependent on neuropilin-associated signaling [ 134 ]. Suppressing the activity of VEGF-VEGFR2-NRP-1 by bevacizumab could evidently impede the proliferation of VEGFR2-positive GBM cells and induce tumor shrinkage [ 135 ].

Early growth response-1 (EGR1), an tumor angiogenesis-associated transcription factor [ 136 , 137 ], can modulate the neuronal plasticity [ 138 ]. Significantly elevated peritumoral vascular and neuronal density has both been observed in EGR1-positive tumor tissues. Moreover, EGR1 expression in tumor brain metastasis tissues is consistent with the high incidence of neurocognitive impairment reported by patients [ 139 ]. This indicates that EGR1 likely plays a multifaceted role in tumor-associated physiological alterations and their effects on the nervous system, potentially bridging angiogenesis-related processes and neurological manifestations.

These emerging studies have disclosed the elaborate functional relationships between neuronal and vascular architectures [ 140 , 141 ]. Gaining insights into the molecular processes through which the nervous system influences angiogenesis may create new opportunities for deciphering the processes of tumor angiogenesis. This, in turn, may facilitate the discovery of innovative diagnostic biomarkers and therapeutic interventions.

Cancer neurotoxicity

The nervous system frequently receives unintended harm during cancer treatment regimens [ 142 ]. Cancer-induced pain exemplifies a tangible manifestation of nerve-tumor interactions. Acting as biological sentinels within TME, pain signals often serve as the first indicator of tumor presence. Yet as tumors advance, sensory neural networks undergo structural rewiring, triggering the rapid progression of pain into severe or chronic states. This pathological shift not only intensifies patient discomfort but also impairs quality of life by disrupting daily function and emotional stability [ 143 ].

Several reviews have confirmed that long-term anti-cancer treatment, such as chemotherapy, could induce neuropathic changes, thereby compromising therapeutic outcomes [ 144 , 145 ]. Moreover, Mattar et al. pointed that chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent adverse effect of some chemotherapy agents, which threatens cancer survival rate [ 146 ]. The occurrence of CIPN frequently leads to dose reduction or premature discontinuation of anti-cancer drugs, consequentially limiting the therapeutic efficiency [ 147 ]. The neuronal cytoskeleton is indispensable for preserving the structural integrity and physiological function of nervous system [ 148 ]. Chemotherapeutic agents induce substantial alterations to the neuronal cytoskeleton, particularly triggering axonal fragmentation and disrupting the microtubule network. Such perturbations compromise the structural stability of sensory neurons, ultimately impairing the axonal transport [ 149 , 150 ]. Paclitaxel, for instance, binds to β-tubulin in polymerized microtubules, which causes a conformational change and renders these microtubules less dynamic [ 151 ]. Peripheral neuropathy induced by paclitaxel has been confirmed in preclinical models of BC, with molecular data supporting alterations related to cytoskeleton and axon morphology during paclitaxel treatment [ 152 ]. Therefore, preventing neurotoxicity caused by these therapeutic approaches can significantly optimize oncologic care during treatment. Using mouse models of multiple myeloma, Park and colleagues discovered that histone deacetylase 6 inhibitor effectively ameliorates the peripheral neuropathy caused by multiple agents, including cisplatin, oxaliplatin, and paclitaxel [ 153 ]. Duloxetine [ 154 ] and methadone [ 155 ], two neuroregulatory drugs, hold potential to manage neuropathic pain and enhance the life quality of cancer survivors experiencing persistent CIPN. Moreover, several clinical trials have confirmed the therapeutic perspectives of duloxetine against CIPN in patients with cancers, such as breast cancer [ 156 – 158 ]. Another randomized, open-label phase II study conducted by Nakamura et al. proved the preventive effect of goshajinkigan against paclitaxel-induced peripheral neuropath, thereby improving the patients’ survival quality [ 159 ]. In the future, clinicians should gain an in-depth understanding of the molecular mechanisms and clinical manifestations underlying therapeutics-induced neurological injury and pain.

Therapeutic implications

Even though current evidence largely supports the notion that nervous system activation participates in the cancer pathological processes [ 160 , 161 ], translating these findings into targeted cancer treatments requires in-depth investigation. The mechanisms through which neural components drive tumor progression represent the promising targets for therapeutic intervention [ 162 – 164 ]. Preclinical research has increasingly revealed that various non-oncological agents, such as antipsychotic medications, exhibit unanticipated anti-cancer activities [ 165 , 166 ]. More importantly, the potential of repurposing neuroregulatory drugs (e.g., antiepileptic drugs, etc.) as anti-cancer strategies has also been verified in some retrospective and prospective trials [ 167 – 169 ]. Nowadays, in the context of developing therapeutic strategies by targeting the reciprocal signaling between the nervous system and tumors, two approaches merit particular attention. One is directly targeting neuro-tumor regulatory molecules, and the other is indirectly interfering with the interaction between nerves and tumor microenvironmental components [ 170 ].

NGF-TrkA

Recently, accumulating research has highlighted the critical roles of neurotrophins in the intricate networks of inflammation and cancer pathology, demonstrating their substantial influence on tumor progression and treatment [ 171 , 172 ]. Among the most extensively-studied neurotrophins, NGF exhibits the ability to bind with tropomyosin-related kinase A (TrkA)-a receptor frequently detected on multiple cancer cell populations [ 173 ]. In the context of inflammation, NGF could elicit the cytokine secretion from immune cells while augmenting the sensitivity of sensory neurons. These dual actions collaboratively contribute to pain hypersensitivity in inflamed tissues [ 174 , 175 ]. Simultaneously, NGF drives tumor progression by fostering cancer cell proliferation and impeding apoptotic processes. Additionally, NGF can trigger the synthesis of pro-angiogenic factors and regulate the microenvironment, culminating in enhanced cellular mobility and invasive potential [ 176 , 177 ]. Thus, targeting NGF and its receptor signaling can provide a new direction for cancer therapy.

In prostate cancer, activation of NGF-TrkA axis drive cancer progression and androgen-resistance [ 178 ]. Specific inhibition of NGF and its corresponding receptors holds promise for multiple therapeutic effects. Such approaches may effectively curtail neural infiltration within TME, impede the proliferative capacity of cancer cells, and ameliorate cancer-associated pain syndromes [ 179 ]. Similarly, genetic or pharmacologic blockade of NGF markedly inhibit cell differentiation and overcome castration resistance in neuroendocrine prostate cancer [ 180 ]. In oral mucosal carcinomas, the NGF secreted from tumor cells drives phenotypic reprogramming of nociceptive neurons to promote calcitonin gene-related peptide (CGRP) biosynthesis. Pharmacological inhibition of NGF-CGRP with antimigraine agents (e.g., rimegepant) has been shown to disrupt the bidirectional crosstalk between malignant cells and sensory nerves. This intervention not only abrogates pro-tumorigenic neuro-immune signaling but also potentiates the anti-neoplastic efficacy of nutrient-deprivation therapies [ 181 ]. During bone TME, consumption of excessive hydrogen ions may impede hydrogen ion-mediated neural activation for pain generation, and meanwhile suppress tumor growth by blocking the NGF/TrkA signaling axis [ 182 ]. Thus, targeting the NGF-TrkA axis with TrkA inhibitors like larotrectinib or entrectinib exhibits concentration-dependent therapeutic efficacy against cancers [ 183 ]. Preclinical studies show that the small-molecule inhibitor binds tightly to the ATP-binding pocket of TrkA with high affinity, suppressing downstream extracellular signal regulated kinase (ERK) and AKT signaling. The onset of pharmacologic effect occurs within 4 h of treatment, as evidenced by reduced phosphorylation of TrkA and its downstream effectors (e.g., ERK, AKT) [ 184 ]. Notably, pharmacodynamic variability is observed in tumors with NTRK fusion mutation [ 183 ]. Some TrkA mutations, like TRKA G667C and TrkA G595R mutations, displays the resistance to TRK inhibitors [ 185 ]. Additionally, intratumoral heterogeneity may lead to uneven drug distribution and resistance [ 186 ]. These studies highlight the need to stratify the TrkA profiles before application of TrkA inhibitors.

Because of the shared sequence in kinase domains of TrkA, TrkB, and TrkC [ 187 ], TrkA inhibitors frequently exhibit off-target binding to TrkB and TrkC, which are predominantly localized in the central nervous system. This might lead to dose-dependent on-target toxicities, including neuropathy, as TrkB/C signaling is critical for neuronal survival and axonal maintenance [ 188 – 190 ]. Moreover, unintended inhibition of VEGF signaling has been reported for some Trk inhibitors, resulting in antiangiogenic risks during differentiation of vascular endothelial cells [ 191 ]. To mitigate these effects, next-generation selective TrkA inhibitors (e.g., repotrectinib) should be developed. Additionally, novel drug delivery systems (DDS), such as iron-based metal-organic frameworks (Fe-MOFs), have been engineered for the loading of TrkA inhibitors. This system exhibits high biocompatibility and serves as an ideal platform for the controlled release and accumulation of TrkA inhibitors in cancer tissues, ultimately achieving effective tumor eradication with enhanced safety profiles [ 192 ]. Nevertheless, these findings have not been confirmed in clinical samples, and the critical parameters such as the optimal dosage and administration schedule of TrkA inhibitors for immune modulation still need to be clarified.

BDNF-TrkB

BDNF and its receptor tropomyosin-related kinase B (TrkB) cooperatively regulates the development of neuron-tumor synaptic connections [ 193 ]. Moreover, BDNF/TrkB axis has been reported to exhibit upregulation in different cancers, and activate multiple oncogenic signaling pathways, including MAPK and PI3K/AKT [ 194 , 195 ]. In glioma, neural activity stimulates the tumor progression via paracrine factors like BDNF. Blockade of TrkB obviously eliminates BDNF-mediated formation of glioma synapses and substantially extends survival in glioma xenograft models [ 196 ]. The upregulation of BDNF in astrocytes by estradiol efficiently initiates TrkB signaling in BC cells, subsequently facilitating their invasive capacity through activating PI3K/AKT signaling. Estradiol deprivation or TrkB inhibitor might offer potential therapeutic alternatives for the management of breast cancer brain metastases [ 197 ]. It is hypothesized that BDNF/TrkB-targeted therapy may exhibit therapeutic efficacy for human tumors with TrkB overexpression or mutations.

However, anti-BDNF antibodies may disrupt the physiological BDNF-TrkB interaction in healthy tissues, leading to cognitive impairment [ 198 ] and mood disorders [ 199 ], as BDNF is critical for synaptic plasticity and neurogenesis [ 200 ]. Meanwhile, Donovan observed the localized expression of BDNF and TrkB in the cardiac and skeletal muscle vasculature [ 201 ]. Disruption of TrkB by inhibitors might lead to coronary vascular disease [ 202 ] or neonatal death [ 203 ] during development. To minimize these off-target effects, more tissue-specific targeting strategies should be explored to enhance the biological safety and clinical efficacy of BDNF-TrkB blocking reagents.

GABA

As the principal inhibitory neurotransmitter within CNS, γ-Aminobutyric acid (GABA) exerts its functional effects by binding to GABA-A and GABA-B receptors in mediating hyperpolarization of postsynaptic membrane and suppressing neuronal excitability [ 204 – 206 ]. The signaling network modulated by GABA plays diverse and critical roles in multiple physiological and pathological processes, such as tumor progression, pain, and neural infiltration [ 207 ]. A thorough analysis of GABAergic system is expected to provide new directions for identifying innovative targets in the fields of cancer treatment.

Tetzlaff and colleague observed that there is a significant recruitment of excitatory glutamatergic neurons and inhibitory GABAergic interneurons in GBM patient-derived xenograft and neuronal co-culture models [ 90 ]. Moreover, modulation of GABA neurotransmission has been shown to impact the growth dynamics of GBM spheroids and their responsiveness to conventional therapeutic strategies [ 208 ]. Accordingly, the benzodiazepine lorazepam increases glioma cell proliferation and growth through enhancing GABA-mediated signaling [ 209 , 210 ]. Downregulation of GABA receptor π subunit (GABRP) in PDAC cells obviously attenuates the growth-promoting effect by GABA [ 211 ]. As a key GABA-degrading enzyme, 4-aminobutyrate aminotransferase (ABAT) overexpression has been shown to suppress malignant phenotypes in non-small cell lung cancer (NSCLC) by reducing GABA accumulation [ 212 ]. Meanwhile, inhibition of γ-aminobutyric acid transporter-1 (GAT-1), a transporter of GABA, significantly reverses the development of cancer-induced bone pain [ 213 ].

Within TME, GABAergic signaling is operational and exerts the immunosuppressive functions, thus facilitating cancer progression [ 214 ] and immune escape [ 215 ]. GABA and its receptor-mediated signaling exerts profound influences on core immune functions, such as immune cell infiltration, cell activation and cytotoxic responses, and participates in various inflammatory diseases, including cancers [ 216 , 217 ]. Activation of the GABA-GABA-B signaling axis was found to induce β-catenin activation, which in turn promotes tumor cell proliferation and impedes the intratumoral infiltration of CD8 + T cells. Preclinical studies in mouse models have demonstrated that targeting GABA or GABA-B notably improve the therapeutic sensitivity to immune checkpoint inhibitor anti-PD-1 [ 218 ]. To systematically characterize the neuro-immune cell subtypes within GBM microenvironment, Sun et al. employed scRNA-seq and revealed that GABA-associated cellular clusters are important in orchestrating immune response and immunotherapeutic interventions. Specifically, their findings indicate that targeting tissue inhibitor of metalloproteinase 1 (TIMP1), a molecule linked to GABAergic signaling, may disrupt the pro-tumoral functional phenotype of M2 macrophages, thereby reversing immunosuppressive state and potentially enhancing the efficacy of immunotherapies [ 219 ]. The preliminary in vitro experiments of GABA-targeted strategies have shown promising results, but in vivo validation and safety evaluation are still required.

NLGN3

Neuroligin-3 (NLGN3), a primary synaptic protein [ 220 ], is regarded as a crucial neuronal-derived factor driving neuronal activity-dependent GBM progression. Soluble NLGN3 secreted from neurons and oligodendrocyte precursor cells is sufficient to facilitate the proliferation of high-grade glioma cells by activating several oncogenic pathways (e.g., PI3K-mTOR pathway), and its expression showed a negative correlation with patients’ prognosis [ 221 ]. Accordingly, Derks’s group observed that low NLGN3 expression in diffuse glioma patients is associated with diminished global brain oscillatory activity and correlated with improved progression-free survival (PFS) [ 222 ]. A-disintegrin-and-metalloprotease family (ADAM) functions as the putative proteases responsible for NLGN3 ectodomain shedding [ 223 ]. Within GBM microenvironment, reduced secretion of NLGN3 by ADAM10 inhibitors expectedly suppresses cancer cell growth and prevents tumor recurrence following surgical resection [ 224 ]. Similarly, depletion of NLGN3 down-regulates several synapse-related factors in glioma cells, and substantially blocks the growth of high-grade glioma xenografts [ 225 ]. Targeting NLGN3-mediated cognitive regulation may enhance the therapeutic efficiency in neuro-oncology [ 226 ]. In the future, elucidating the intricate molecular foundations of NLGN3’s function in neuro-oncology holds promise for guiding the design of novel therapeutic interventions.

Glutamate and glutamate receptors

As one of the primary excitatory neurotransmitters in CNS, glutamate has been demonstrated to exert a critical role in GBM pathogenesis. Beyond its established function in normal brain development [ 227 ], glutamate and its receptors synergistically promotes proliferation and migration of glioma cells [ 228 ]. In the GBM microenvironment, the secretion of glutamate from neurons, tumor cells or other cells could trigger intracellular calcium ion accumulation, tumorigenesis and exacerbating glioma-associated epilepsy [ 229 – 232 ]. Inhibition of glutamate-dependent glioma-neuronal connectivity is beneficial to restrain tumor cell progression [ 233 ]. A phase Ib/II randomized, open‑label trial was recently conducted to assess the efficiency of glutamate signaling inhibitors alongside with chemoradiotherapy for the treatment of newly diagnosed GBM patients. The favorable tolerance observed in participants supports the feasibility of integrating anti-glutamine agents with standard chemoradiotherapy [ 234 ]. Considering the influence of synaptic glutamate concentrations on two postsynaptic glutamate receptor subtypes [ 235 ], targeting specific subtypes of these receptors could improve the therapeutic efficacy against cancers.

On nearby neurons, abnormal glutamate accumulation activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, causing neuronal hyperactivity [ 236 ]. The AMPA glutamate receptors are critical for mediating fast excitatory synaptic transmission within CNS. Their dynamic expression on the postsynaptic membrane has been linked to the initiation and sustainment of long-term potentiation and long-term depression-two forms of synaptic plasticity that underlie learning and memory mechanisms [ 237 ]. Surprisingly, AMPA receptors also locate on tumor microtubes of GBM cells. Heuer et al. revealed that GBM cells can acquire growth and invasion signals from presynaptic neurons via AMPA receptor-mediated pathways. Inhibition of AMPA receptor activity by antiepileptic perampanel significantly suppress glioma cell proliferation and invasion in vivo and in vitro [ 238 – 241 ]. Meanwhile, administration of perampanel in patients with brain neoplasms also restraints the cancer-associated epileptic seizure [ 242 , 243 ]. Recently, several independent trials have confirmed the clinical efficacy of perampanel in patients with progressive glioma. Perampanel treatment reduces synaptic communication and tumor growth by targeting glutamatergic activity [ 244 , 245 ]. Notwithstanding, additional randomized trials are warranted to assess the impact of perampanel on tumor clearance and patients’ survival time [ 246 ].

Unexpectedly, antagonists of N -methyl- d -aspartate (NMDA) glutamate receptors elicit cognitive side effects by perturbing physiological glutamate signaling within cognitive neural subsystems [ 247 ]. Severe adverse effects-including sedation, hallucinations, and cardiac instability-have restricted the application of glutamate receptor antagonism in outpatient settings [ 248 ]. Ceftriaxone, a cephalosporin antibiotic with activity against glutamate release, might induce gut microbiota dysbiosis [ 249 ] and promote antibiotic resistance [ 250 ], thereby limiting its long-term clinical utility. Thus, understanding tumor-specific targets for glutamate receptor antagonists is imperative for identifying optimal glutamatergic strategies in cancer treatment.

Future perspectives

Application of MiRNAs in neuro-oncology

MicroRNAs (miRNAs) are a class of small non-coding RNAs that mediate post-transcriptional gene regulation [ 251 – 255 ]. To date, these molecules have been the subject of extensive research, with numerous studies underscoring their functional relevance in the field of nerve-tumor interactions [ 256 , 257 ]. The HOX transcript antisense intergenic RNA (HOTAIR), an oncogenic long non-coding RNA (lncRNA), exerts its function by sequestering specific microRNAs (miRNAs), thereby modulating the expression of downstream target genes implicated in neurotransmitter physiology and the crosstalk between neural cells and tumors [ 258 ]. Chiyomaru et al. pointed that HOTAIR is a direct target of miR-141, with these two molecules exerting opposing regulatory effects on tumor progression [ 259 ]. Meanwhile, ectopic overexpression of miR-141 markedly impedes the recruitment of HOTAIR to EZH2 and their subsequent binding to the BDNF gene promoter. In turn, this abrogates the repressive effect of HOTAIR-EZH2 complex on BDNF transcription, thereby promoting the differentiation of amniotic epithelial stem cells into dopaminergic neuron-like cells [ 260 ]. NOTCH-dependent signal regulates the development and differentiation of many organ systems, including cell differentiation and neurogenesis [ 261 ]. Following infection into glioma cells, the neurotropic herpes simplex virus 1 (HSV-1) triggers the activation of intratumoral neurogenic locus notch homolog (NOTCH) signaling through encoding miR-H16. Notably, suppression of NOTCH pathway using gamma secretase inhibitors (GSIs) significantly enhances the sensitivity of cancer cells to oncolytic HSV-based therapy [ 262 ]. Recent reports have identified several cancer-associated miRNAs implicated in neuropathic pain, such as miR-300 [ 263 ]. Overexpression of miR-300 markedly mitigates cancer-induced neuropathic pain, which is achieved through the targeted suppression of its downstream effector high mobility group box 1 (HMGB1) [ 264 ]. Zhu’s group further observed that miR-330 is highly-upregulated in spinal dorsal horn (SDH) of nude mice suffering from pancreatic cancer-associated pain. Silencing of miR-330 restores the expression of GABABR2 and mitigates abdominal hyperalgesia induced by pancreatic cancer [ 265 ]. The above evidence provides us with broad insights into the roles of miRNA-based signaling in the field of neuro-tumor communication.

Neuro-tumoral crosstalk on tumors of similar origin

Tumors with a similar origin represent critical research models for unraveling the conserved mechanisms governing tumor initiation and progression, while also refining diagnostic and therapeutic strategies. Their value is particularly pronounced in molecular subtyping and cross-cancer therapeutic applications [ 266 , 267 ]. For example, neuroectodermal-derived cancers, such as GBM and medulloblastoma, arise from neural precursor cells or differentiated neural tissues, which confers inherent molecular and functional associations with the nervous system [ 268 , 269 ]. In contrast to non-neural origin cancers (e.g., BC, PDAC), these neuroectodermal-derived cancers engage in direct crosstalk with neighboring neural cells (e.g., neurons, Schwann cells) via some signaling factors (e.g., BDNF/TrkB, NOTCH). These interactions culminate in the formation of distinct “neuro-tumoral niches” that affect tumor initiation, progression, and therapeutic responsiveness. Meyer et al. has employed an established native GBM model and observed that tumor expansion is directly relevant to glutamatergic signaling and neuronal hyperactivity [ 232 ]. Similarly, medulloblastoma cells express the functional components of NMDA glutamate receptors [ 270 ]. Treatment with NMDA-receptor antagonists significantly decrease the invasive capacity of GBM [ 271 ] and medulloblastoma [ 272 ] cells. Exploring the shared core features of homologous tumors ensures that our findings are directly translatable to clinical scenarios where neuro-tumoral crosstalk is most biologically relevant.

Heterogeneity

The pattern of neuro-immune modulation is strictly context-specific, with its characteristics determined by three key factors: neural signal types, immune cell subset heterogeneity, and TME dynamic status. During chronic stress, adrenergic signaling drives sympathetic nervous system activation, which in turn triggers the release of neurotransmitters (e.g., norepinephrine) that specifically target MDSCs. Through binding to β2-adrenergic receptors on MDSCs, norepinephrine could upregulate the expression of immunosuppressive molecules (e.g., arginase-I and PD-L1) to suppress antitumor CD8+ T cell function [ 273 ]. Subsequent activation of β2-adrenergic receptor signaling promotes MDSC accumulation and survival via STAT3 phosphorylation, thereby facilitating the formation of pro-survival and immunosuppressive microenvironmental conditions that favor tumor progression [ 274 ]. These effects could be amplified in hypoxic TME, where hypoxia via HIF-1α dramatically redirects the differentiation of MDSCs toward immunosuppressive tumor-associated macrophages [ 275 ].

However, parasympathetic nerves-via acetylcholine signaling-exerts multiple regulatory effects on the immune response. In most cases, acetylcholine suppresses the cytotoxic function of CD8 + T cells and the inflammatory response of macrophages, contributing to tumorigenesis [ 276 ]. Acetylcholine-induced persistent high expression of inhibitory receptors is also detrimental to T cell and impairs their cytotoxic activity, ultimately exacerbating immune suppression [ 277 ]. Inversely, some studies have reported that acetylcholine activates α7 nicotinic acetylcholine receptors (α7 nAChRs) on macrophages to promote M1 polarization and prevent immunosuppressive states [ 278 ]. Acetylcholine released from T cells elicits autocrine alterations in intracellular Ca²⁺ homeostasis, thereby facilitating the activation and proliferation of neighboring T cell populations [ 279 ].

Likewise, GR signaling has been extensively documented to participate in the progression of GBM, yet its specific functions are not consistently pro-tumorigenic as previously reported [ 37 ]. Although the GR agonist DEX is widely utilized to alleviate tumor-associated cerebral edema in GBM patients [ 280 , 281 ], administration of DEX has unexpectedly shown a negative correlation with treatment outcomes, a finding that has been validated by independent research teams [ 282 , 283 ]. Meanwhile, concurrent DEX treatment significantly impairs lymphocyte functional capacity, ultimately restricting anti-GBM immune responses during immunotherapy [ 284 ]. Based on these conflicting evidence and research limitations, several unresolved controversies persist in the field of GR signaling in GBM: (1) The role of GR signaling shows subtype-specific differences. For example, DEX displays the different functions in PTEN-mutant and PTEN-wildtype tumor cells [ 285 ]. (2) The clinical application values of GR signaling remain unclear-whether GR signaling can serve as a favorable prognostic marker or therapeutic target still requires verification through more large-scale prospective cohort studies [ 283 ]. (3) The interaction between GR signaling and perioperative treatment, as well as disease grade, has not been fully investigated [ 286 ]. These unanticipated outcomes may be attributed to the occurrence of DEX-related adverse effects, such as leukocytosis [ 287 ] and immune suppression [ 288 ], which have compromised the clinical efficacy of DEX.

In addition, immune cell heterogeneity further dictates the outcome of neuro-immune crosstalk. For example, different T cell subpopulations may exhibit distinct responses to same neurotransmitter. Due to the divergent neurotransmitter receptor profiles between naïve/resting and activated T cells, certain neurotransmitters (e.g., dopamine) exert activating effects on naïve/resting T cells, while exerting suppressive effects on TCR-activated or cytokine-activated T cell lineage [ 289 ]. In future, rlucidating the complex crosstalk between neural signals and TME dynamics is critical for translating the therapeutic potential of neuro-immune axis into effective anti-cancer strategies.

Tumor-specific variability

Pan-cancer analyses frequently reveal prominent alterations in the abundance and kinetic characteristics of tumor-infiltrating immunoregulatory components in diverse cancer types before and after therapeutic intervention [ 290 ]. For instance, TRPV1, a non-selective cation channel predominantly expressed in sensory neurons and subsets of tumor cells, mediates neuro-tumor crosstalk through Ca²⁺ influx-dependent downstream signaling cascades [ 291 ]. Notably, TRPV1 exhibits context-dependent functional roles across different tumor types. In Lewis lung carcinoma, high TRPV1 expression is detected in both tumor cells and adjacent sensory neurons: activation of neuronal TRPV1 promotes the secretion of SP and CGRP, which in turn drive cancer cell growth [ 292 , 293 ]. In PDAC, inhibition of sphingosine-1-phosphate receptor 1 (S1PR1) downregulates TRPV1 and CGRP expression, thereby suppressing tumor progression and mitigating PDAC-associated neuropathic pain [ 294 ]. In contrast, in other tumor entities (e.g., high-grade astrocytomas), TRPV1 activation correlates with improved prognosis, as TRPV1 agonists released by neural precursor cells can trigger tumor cell death via excessive Ca²⁺ influx [ 295 ]. These conflicting findings underscore the tissue-specific dual functionality of TRPV1 in mediating neuro-tumor interactions.

Conclusion

Recent advances have underscored the critical roles of neuro-tumor interactive signaling in disease pathogenesis, with emerging evidence highlighting the dynamic crosstalk between neuronal remodeling and cancer cells. During neuronal firing, ions are discharged, often considered as metabolic byproducts following synaptic transmission. These include sodium and potassium ions, which may engage in functional interactions with tumor cells within the microenvironment. Within TME, neural-derived signaling molecules, including ionic byproducts, can trigger the activation of conserved signaling cascades, which are instrumental in driving tumor progression and shaping therapeutic responses. For instance, neuronal signaling molecules may facilitate tumor advancement by modulating the expression of genes involved in apoptotic regulation and proliferative control.

The interplay between neural activity and cancer cells emerges as an intricate but pivotal research frontier. While the modulatory function of the nervous system in tumorigenesis and therapy has been well-documented, the precise molecular and cellular mechanisms underpinning this interaction remain not fully deciphered. In-depth investigations in this domain not only aid in unraveling tumor biological characteristics but also furnish novel perspectives for therapeutic innovation. Future studies investigating the mechanistic basis of neuro-tumor interactions may uncover additional potential therapeutic targets and intervention strategies.

Acknowledgements

Not applicable.

Author contributions

Wang X, Tang H and Xu Z constructed and designed the manuscript. Wang X, Thakur A, Zhang K and Zhan C wrote the original draft preparation. Yan Y, Li L, Li T, Li J and Hu K reviewed the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82473299), the Natural Science Foundation of Hunan Province (2023JJ3089, 2024JJ5560), the Guangdong Basic and Applied Basic Research Foundation (2023A1515111116), the Shenzhen Foundation of Science and Technology (JCYJ20230807151308018).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

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

Contributor Information

Xiaokang Wang, Email: kangtae_won@i.smu.edu.cn.

Zhijie Xu, Email: xzj1322007@csu.edu.cn.

Kuan Hu, Email: kuan.hu@csu.edu.cn.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.