Abstract
Abstract
Neural regulation of cancer extends beyond anatomical innervation: tumours receive systemic neural and neuroendocrine inputs and locally produce and decode neurotransmitters and neuropeptides. We propose the Tumour Neurotone (TN) as a tumour-level state of neurochemical regulation generated by the combined actions of these signals across malignant, immune, stromal and vascular compartments, shaping proliferative signalling, metabolic adaptation, immune escape, tissue remodelling, dissemination and treatment response. Biologically, a TN state reflects the context-dependent, spatially organised and relatively persistent configuration of neuroactive ligand availability; cell-type-specific signalling competence, including receptors, transporters and metabolic enzymes; proximal pathway engagement; and downstream cellular responses. TN is therefore not synonymous with tumour innervation, nerve density, an instantaneous neurochemical profile, neuroimmune crosstalk or the broader field of cancer neuroscience; it is a narrower state model intended to capture functional organisation beyond any single neurotransmitter pathway. We synthesise evidence across proliferative signalling, metabolic plasticity, immune regulation, sensory–neuropeptide circuits, neural remodelling, bioelectrical communication, vasculo–stromal organisation and circadian timing. Although many constituent mechanisms are causally supported, the existence and predictive value of integrated TN states have not yet been validated clinically. We therefore specify three criteria for assigning a TN state: temporal reproducibility, predictive value beyond individual components and established tumour covariates, and coherent change after targeted perturbation. We also provide a longitudinal experimental workflow, framework-specific predictions and falsification criteria, and an evidence-graded appraisal of neuromodulatory interventions.