Tumor innervation in non-central nervous system tumors: origins, mechanisms, and phenotypic plasticity

The peripheral nervous system has emerged as an important regulator of solid tumor biology. We synthesize recent advances in cancer neuroscience, focusing on three interconnected themes: the cellular origins of tumor-associated nerves, the molecular mechanisms that govern neural recruitment and remodeling, and the resulting phenotypic plasticity within the tumor microenvironment. Tumor innervation arises through axon extension from pre-existing nerves, recruitment of neural precursors, and neuron-like transdifferentiation of non-neuronal cells. These processes are driven by neurotrophic factors, axon guidance cues, extracellular vesicles, and stress-associated pathways. The functional consequences of innervation are context-dependent, with sympathetic, parasympathetic, and sensory inputs exerting distinct effects across tumor types and stages. We conclude by outlining key challenges and future directions for therapeutic translation.