Neuron–tumor communication as a target for neuromodulatory drug delivery in cancer

The presence of nerves within tumors was largely unexplored in the early 19 th and 20 th century, with contemporary pathology texts generally considering tumors to be devoid of nerves. However, observations of tumor-associated pain and intratumoral nerve fibers challenged this view, prompting questions about their role in neoplastic tissue. As early as 1897, Young Y. reported nerves in various non-neural tumors, including breast and cervical carcinomas, sarcomas, myxomas, and metastatic carcinomas, providing early histological evidence of neural elements within tumors (1). This seminal study raised an important question of whether intratumoral nerves represented pre-existing neural structures incorporated during tumor growth or reflected active neural changes associated with neoplastic development.To address this question, investigations in the late 1920s and early 1930s began to explore the origin and biological significance of these intratumoral nerves. In 1928, Herzog E. investigated the presence of nerve fibers in 100 neoplasms and proposed that intratumoral nerves represented pre-existing nerves incorporated into infiltrating neoplastic tissue. His observations suggested that the distribution of nerves was related to the pattern of tumor invasion, supporting the view that their presence could result from the incorporation of normal neural structures during tumor growth (2). In 1929, Oertel H. proposed a different interpretation, proposing that human carcinomas possessed an intrinsic neural organization, with nerve fibers closely associated with the tumor stroma, blood vessels, and parenchymal elements. This raised the possibility that the relationship between nerves and tumors might extend beyond passive entrapment (3). In 1930, Martynow W. further challenged the concept of simple nerve incorporation by suggesting that nerve fibers within carcinomas could be newly formed. He also described degenerative changes in these fibers, indicating that intratumoral nerves might undergo active remodeling in response to the tumor microenvironment (4).In 1931, Oertel H., Nye H., and Thomlinson B. provided additional observations on nerve fibers within human tumors, further supporting the presence of an organized neural component within neoplastic tissue (5). In 1933, Ryrie synthesized these observations in his original investigation of the anatomical and physiological relationship between nerve fibers and neoplasms. He considered several possibilities, including the incorporation of pre-existing nerves into tumors, the formation of new nerve fibers within neoplastic tissue, and degenerative and regenerative changes resembling those observed after peripheral nerve injury. These observations raised the possibility of an active interaction between nerves and malignant tissue. Nevertheless, Ryrie G. concluded that the available evidence did not justify assuming a trophic influence of nerves on malignant cells (6).Two studies published in 1982 and 1985 investigating neuroendocrine biomarkers also provided early biochemical evidence linking neural biology and cancer, demonstrating significantly elevated serum neuron-specific enolase (NSE) levels in patients with small-cell lung cancer (SCLC) (7,8). In 1982, Carney et al. first reported that serum NSE was elevated in 69% of newly diagnosed patients with SCLC (n = 94) compared with controls, with a higher prevalence in extensive-stage disease (87%) than limited-stage disease (39%). Mean NSE levels were significantly higher in extensive-stage disease (59 ng/ml vs 13.8 ng/ml), increased further with metastatic burden (84% of patients with 1-2 sites and 100% of those with ≥3 sites), and showed a strong correlation with chemotherapy response. SCLC cell lines derived from patients also consistently expressed high levels of NSE (7). In a comparable study, Akoun et al. found that serum NSE levels were elevated in 65.1% of patients diagnosed with SCLC (n = 43), with significantly higher mean levels in extensive-stage disease (50 ng/ml) than in limited-stage disease (16 ng/ml), while levels were much lower in non-SCLC (11 ng/ml) and noncancerous lung disease (7 ng/ml). NSE closely correlated with tumor burden and showed dynamic changes during chemotherapy, with higher early levels (>100 ng/ml) associated with better treatment response (8). This mechanism was subsequently revealed in a 2022 study (Figure 1), which demonstrated that NSE interacts with and suppresses neuroblastoma suppressor of tumorigenicity 1 (NBL1), thereby relieving NBL1-mediated inhibition of BMP2 signaling. This interaction enhances BMP2-BMPR1A signaling and activates the BMP2/Smad/ID1 pathway, ultimately promoting malignant characteristics of SCLC (9). Keeping track of these conceptual advances, a growing body of experimental evidence (detailed in section 2) have provided evidence of functional neuron-tumor interactions across multiple cancer types. Studies in human specimens have identified such interactions in squamous cell carcinoma (10), breast cancer (11), gastric cancer (12), pancreatic ductal adenocarcinoma (13), lung adenocarcinoma (14), prostate cancer (15), and diffuse midline glioma (16,17). SCLC has been investigated using human specimens, ex vivo electrophysiological and co-culture models (18), and in vivo models (19), while glioblastoma (20,21), glioma (22), diffuse midline glioma (16), gastric cancer (23), and breast-to-brain metastasis (24), have been studied primarily using in vitro and in vivo models. Evidence from these studies shows that neural signaling influences tumor growth, invasion, metastasis, and proliferation, while inhibition through pharmacological or genetic targeting of CHRM3, AMPARs, NMDARs/GRIN2B, GRIN2D, GABA receptors, NKCC1, CGRP, β-adrenergic signaling, and sensory or sympathetic neuron ablation has demonstrated therapeutic potential (12,18,22,23,25).Several recent reviews have synthesized the rapidly expanding field of cancer neuroscience, encompassing interaction mechanisms, neuron-tumor synapses and pseudosynaptic interfaces, neuroimmune and paracrine signaling, neural regulation of tumor progression and metastasis, and emerging therapeutic strategies targeting neural dependencies (26)(27)(28)(29). Clinical translation has also been considered, with emphasis on drug repurposing, biomarker development, and clinical trial designs to advance neuroscience-informed cancer therapies (30). These reviews have already established the biological significance of neuron-tumor communication and highlighted its potential as a therapeutic target. However, the potential of neuron-tumor communication to inform and shape targeted drug-delivery strategies remains largely unexplored.Following a careful review of the literature and registered clinical trials (Clinicaltrials.gov), we identified a growing but still limited effort to modulate neural signaling in cancer, with studies predominantly investigating β-adrenergic blockade, prostaglandin pathway inhibition, and local autonomic denervation. Clinical studies of propranolol (NCT01847001, NCT02420223, NCT00888797, NCT03384836, NCT00502684, NCT03838029, NCT04493489, NCT04682158, NCT05741164, NCT03919461, NCT05979818, NCT06839144, NCT07125391, and NCT07311915), etodolac (NCT00888797, NCT00502684, NCT03838029, NCT03919461, and NCT06839144), and botulinum toxin A (NCT01822210), administered predominantly systemically, highlight the therapeutic relevance of modulating neural signaling in cancer, although the clinical evidence remains preliminary and varies across approaches. In addition, glutamate-receptor antagonists, including riluzole (18), and NBQX (31), illustrate further pharmacological strategies for modulating tumour-neural communication, with varying levels of preclinical and clinical maturity. Propranolol-conjugated NP41-functionalised nanoparticles provide proof of concept for nerve-directed drug delivery in prostate cancer, validation across tumour types and systematic assessments of efficacy, selectivity, and neural safety remain necessary (32). Despite these contributions, the field of neuromodulation in cancer remains in its early stages, with key challenges in translating mechanistic insights into selective and clinically effective interventions. Therefore, in this Opinion, we propose the tumor-nerve interface as a potential target and discuss its implications for neuromodulatory drug delivery. Early experimental and clinical studies established that autonomic innervation can regulate tumor progression. In prostate cancer xenografts (PC-3), transgenic mouse models (Hi-Myc), and human prostate adenocarcinoma tissues (n = 43), sympathetic and parasympathetic nerves were found to exhibit distinct effects on tumor growth. While parasympathetic cholinergic nerve fibers penetrated tumors and encouraged invasion and metastasis, chemical or surgical sympathectomy and genetic ablation of stromal β2-and β3-adrenergic receptors significantly inhibited early tumor development. Analysis of human specimens further showed that high densities of sympathetic and parasympathetic nerve fibers were linked to aggressive clinicopathological features, such as increased levels of prostate-specific antigen, extracapsular extension, biochemical recurrence, and poor clinical outcomes (15). Similarly, in mouse models of gastric cancer (INS-GAS) and human gastric cancer specimens (n = 137), vagal cholinergic signaling was shown to drive tumorigenesis via muscarinic acetylcholine M3 receptor activation and Wnt pathway signaling. Surgical vagotomy, botulinum toxin type A (Botox), or pharmacological/genetic inhibition of the M3 receptor significantly reduced tumor growth, enhanced chemotherapy efficacy, and prolonged survival. Analysis of human specimens further showed that increased neural density correlated with advanced tumor stage and activated Wnt signaling, while clinical evaluation of patients with gastric stump cancer (n = 37) showed that vagotomy was associated with a reduced risk of gastric cancer (12).Subsequent studies expanded this concept to sensory and sympathetic neural pathways across several tumor types (13,(33)(34)(35)(36). In pancreatic ductal adenocarcinoma (PDAC), TRPV1⁺ sensory neurons promoted tumor development through neurogenic inflammation and reciprocal neuron-tumor signaling. In mouse models, neonatal capsaicin-mediated sensory neuron ablation significantly reduced pancreatic intraepithelial neoplasia formation, prevented perineural invasion and central nervous system inflammation, and prolonged survival (7.8 vs. 4.5 months, p = 0.001) (13). In a different study, sympathetic neural signaling also promoted PDAC progression through β-adrenergic mechanisms and was associated with increased intratumoral nerve density and brainderived neurotrophic factor (BDNF) expression (36). In basal cell carcinoma, sensory nervesmaintained Hedgehog signaling in Gli1-expressing touch dome progenitor cells adjacent to Merkel cells. Surgical denervation significantly reduced touch dome-derived tumor formation without affecting hair follicle-derived lesions (33). In melanoma, sympathetic innervation was shown to promote tumor progression, as chemical sympathectomy with 6-hydroxydopamine significantly reduced tumor burden in B16-F10 models (0.29 vs. 1.02 g, p < 0.05). Denervation also altered the tumor microenvironment, increasing expression of apoptosis-related genes (Bcl-2 and caspase-3) and hypoxia-inducible factor-1α (34).Beyond the effects of pre-existing nerves, evidence emerged that tumors can actively remodel and generate neural components. In human gastric and colorectal carcinomas, cancer stem cells differentiated into functional neuron-like cells expressing MAP2, TUJ, synaptic proteins (SV2A, Synapsin), and autonomic markers including TH⁺ sympathetic and VaChT⁺ parasympathetic neurons. In xenograft models, human neurons (NuMA⁺) originated from cancer stem cells and incorporated into the tumor ganglia and tissues, while silencing MAP2 significantly inhibited tumor growth in vivo (p < 0.01) and decreased neuronal production without affecting proliferation (37).Consistent with these experimental findings, clinical studies have linked tumor-associated innervation with aggressive disease across multiple cancers. In upper aerodigestive tract squamous cell carcinoma, small peripheral nerves (<1 mm) were associated with increased perineural invasion, local recurrence, and poor survival (10). In breast cancer, increased tumor-associated nerve density and neurogenesis were associated with higher tumor grade, angiogenesis, and poor survival (11). Mechanistic studies further showed that SLIT2-mediated innervation and substance P/TACR1 signaling promoted tumor invasion, proliferation, circulating tumor cells, and lung metastasis in breast cancer (38). In lung adenocarcinoma, sensory signaling through the pathway promoted tumor growth and progression and was associated with and reduced survival neural regulation of tumor functional communication between neurons and tumor cells have been reported in multiple cancer types. 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