The 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 beta-adrenergic receptor activation, while parasympathetic input exerts dual roles-driving gastric cancer yet protecting against colitis-associated 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 Ca-2(+) 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 beta-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.
[1]Univ Shanghai Sci & Technol, Shanghai 200093, Peoples R China.
[2]Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Orthoped, Shanghai 200080, Peoples R China.
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