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Sensory nerves modulate pain, angiogenesis, and immunity via CGRP and substance P, while functional neuro-glioma synapses enable glutamate–AMPA signaling with calcium-driven oncogenic programs. 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\n[https://doi.org/10.1007/s13402-025-01](https://doi.org/10.1007/s13402-025-01)151-9  \nREVIEW  \nNeural-tumor crosstalk and molecular targeting: mechanisms and therapeutic implications in cancer neuroscience  \nTianhui Hou1,2 · Huaze Ding2 · Guofang Huang1,2 · Tong Meng2 · Dianwen Song1,2  \nReceived: 24 June 2025 / Accepted: 19 October 2025 © The Author(s) 2025  \nAbstract  \nThe nervous system is increasingly recognized as a key regulator of the tumor microenvironment, engaging in bidirectional crosstalk with cancer cells through neurotransmitters, neuropeptides, and synaptic-like connections. Autonomic nerves modulate tumor progression: sympathetic signaling promotes growth, metastasis, and immune evasion via β-adrenergic receptor activation, while parasympathetic input exerts dual roles—driving gastric cancer yet protecting against colitisassociated colorectal cancer through the cholinergic anti-inflammatory pathway. Sensory nerves influence pain, angiogenesis, and immunity, with CGRP and substance P differentially regulating anti-tumor responses. Notably, functional neuro-glioma synapses have been identified, where neuronal glutamate release activates AMPA receptors on tumor cells, triggering Ca²⁺ influx and oncogenic signaling—providing a mechanistic basis for repurposing AMPA antagonists like perampanel. Glial cells, including Schwann cells and astrocytes, support perineural invasion, metabolic coupling, and therapy resistance via neurotrophic factor secretion and extracellular matrix remodeling. Tumor-derived signals reciprocally rewire neural circuits, enhancing innervation and neuroplasticity. Central brain regions, such as the paraventricular nucleus, integrate stress inputs to systemically regulate tumor immunity and metabolism through autonomic output. This dynamic interplay positions the nervous system as a master regulator of cancer biology. Targeting neural-tumor interactions—via β-blockers, neuromodulation, or bioelectronic medicine—offers novel therapeutic strategies. Future precision oncology approaches must consider tumor type, stage, and neural context to effectively disrupt this crosstalk and the emerging concept of cancer-induced nerve injury (CINI) as a novel mechanism of immunotherapy resistance.  \nClinical trial number  \nNot applicable  \nKeywords Cancer neuroscience · Neural-tumor crosstalk · Tumor microenvironment · Neurotransmitters · Glial cells · Targeted therapy  \nTianhui Hou, Huaze Ding and Guofang Huang contributed equally to this work, and all should be considered as first author.  \n􀀍 Tong Meng [mengtong@medmail.com.cn](mengtong@medmail.com.cn)  \n􀀍 Dianwen Song[osongdianwen@126.com](osongdianwen@126.com)  \n1 University of Shanghai for Science and Technology, Shanghai 200093, China  \n2 Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China  \n1 Introduction  \nFor a long time, intratumoral nerves were viewed as passive structural elements—innocent observers in the tumor microenvironment. But accumulating evidence now challenges this notion, revealing that the nervous system actively engages in bidirectional crosstalk with cancer cells, influencing tumor initiation, progression, and metastasis through defined molecular pathways [1] . Far from being mere conduits of electrical signals, neurons and their supporting glial cells have emerged as functional regulators of malignancy, Recent mapping of the brain-wide connectome in human glioblastoma patients has revealed the astonishing extent to  \n1 3  \nwhich tumors integrate into and remodel functional neural circuits [2] .  \nAt the cellular level, neurotransmitters and neuropeptides act directly on tumor cells. Norepinephrine, released by sympathetic nerves, binds β-adrenergic receptors to activate cAMP/PKA and MAPK signaling, driving proliferation, epithelial-mesenchymal transition, and immune evasion in breast, prostate, and ovarian cancers [3, 4]. In c","cbCaim7zb0Szwdve","https://ap.wps.com/l/cbCaim7zb0Szwdve","pdf",1864136,16,"English","# Abstract\n# Introduction\n## Bidirectional neural–cancer crosstalk in the tumor microenvironment\n## Autonomic nerves: sympathetic and parasympathetic signaling\n## Sensory nerves and neuropeptides in tumor regulation\n## Functional neuro-glioma synapses and AMPA receptor targeting\n## Glial cells, perineural invasion, and therapy resistance\n# Conclusion\n## Central and peripheral nervous system regulation of tumor progression","[{\"question\":\"How does the nervous system influence the tumor microenvironment?\",\"answer\":\"It engages in bidirectional crosstalk with cancer cells via neurotransmitters, neuropeptides, and synaptic-like connections that modulate tumor initiation, progression, and metastasis.\"},{\"question\":\"What roles do sympathetic and parasympathetic signaling play?\",\"answer\":\"Sympathetic signaling promotes growth, metastasis, and immune evasion through β-adrenergic receptor activation, while parasympathetic input can have dual effects, including support through gastric cancer and protection against colitis-associated colorectal cancer via cholinergic anti-inflammatory pathways.\"},{\"question\":\"Why is AMPA antagonism discussed as a therapeutic strategy?\",\"answer\":\"Functional neuro-glioma synapses enable neuronal glutamate release that activates AMPA receptors on tumor cells, causing Ca²⁺ influx and downstream oncogenic signaling, providing a mechanistic basis for repurposing AMPA antagonists such as perampanel.\"}]","Neural-tumor crosstalk and molecular targeting - mechanisms and therapeutic implications in cancer neuroscience | PDF",1790115237]