Molecular Targeting of the Peripheral Nerve–Tumor Axis in Extracranial Solid Cancers: Eight Signaling Systems, One Effect—Systematic Review and Multilevel Meta-Analysis

The peripheral nerves that innervate solid tumors communicate with the malignant cells through a restricted set of molecular signaling systems: adrenergic and muscarinic receptors, sensory neuropeptides, neurotrophins and their tyrosine kinase receptors, axon guidance molecules, and nociceptor ion channels. Each has been proposed separately as a therapeutic target but never quantitatively compared with the others. The question is whether one of them dominates—or whether the real target is the axis as a system. We systematically searched PubMed, Scopus, and Web of Science, with four query modules per database, without year or language restriction. We included in vivo studies in mammals, on extracranial solid cancers, with an intervention that modulated tumor innervation, peripheral nerve activity, or neural signaling, and with at least one tumor burden outcome. Of 16,649 unique records, 362 were included, with 1291 experiments and 1437 effects. Blockade of the peripheral nerve–tumor axis reduced tumor burden by −44.8%. In the prespecified primary analysis, on established tumors, the reduction was −52.0% with no significant difference from preventive interventions (p = 0.17). All eight molecular signaling systems responded to blockade, with estimates ranging from −34.3% for TRP channels to −70.2% for glutamatergic signaling. Interventions that activate the axis produced the opposite effect, with a 52.1% increase (95% CI: 32.1 to 75.1) across 253 effects, and bidirectionality was demonstrated within the same molecular system for the adrenergic compartment (−42.8% for blockade vs. 58.1% for activation), axon guidance molecules, and TRP channels. Egger’s test indicated marked small-study effects (slope −1.12; p < 0.001); the estimate remained stable when low-confidence digitized values were excluded (−42.6%). Eight distinct molecular signaling systems, disrupted by methods with nothing in common, produce reductions of a similar magnitude in tumor burden, and stimulation of three of them produces the opposite effect.