Neuronal hijacking of cancer niches: integration, remodeling, evolution

Cancer is a disease of dysregulated multicellular coordination in which transformed cells evade homeostatic constraints to proliferate, invade, and metastasize. Increasing evidence places the nervous system, spanning central and peripheral circuits, within the tumor microenvironment as an active organizer rather than a bystander. Neuronal inputs shape malignant phenotypes through multiple interaction modalities, including paracrine neurotransmitters, neuropeptides, and neurotrophic factors, synapse-like neuron–tumor coupling, tumor-intrinsic bioelectric excitability, nerve-guided invasion/perineural spread, and tumor-driven neuronal remodeling. Through these pathways, neuronal inputs and activity can directly reprogram tumor growth, invasion, stem-like states, and therapy response, while indirectly rewiring immune surveillance, stromal activation, vascular dynamics, and metabolic ecosystems to create permissive niches for progression. Crucially, neuronal signaling is not a unidirectional growth license but a context-encoded control layer whose net effect can flip with receptor/transport configuration, cellular state, and neuroimmune wiring, fueling proliferation, invasion, and immune exclusion in some niches while reinforcing antigen presentation, effector fitness, and tissue-resident cytotoxicity in others. Here, we synthesize a pan-cancer framework for neuro–tumor crosstalk, emphasizing shared mechanistic logic across organ contexts and across primary tumors and metastases within the same neuronal ecological niches. By integrating neuronal signaling with microenvironmental rewiring, this review clarifies how circuit activity and neuroregulatory programs become selectable components of tumor evolution and highlights emerging opportunities to therapeutically target neuro–tumor axes in cancer. Accordingly, translation should move beyond blanket “denervation logic” toward program-selective neural intervention and therapeutic reprogramming guided by niche-resolved biomarkers.