The Role of the Autonomic Nervous System in Oncogenesis: Friend or Foe?

Recent advances in neuro-oncology fundamentally challenge the traditional view of cancer as anarchic cellular proliferation, independent of physiological regulation. This review synthesizes the compelling evidence for bidirectional communication between the autonomic nervous system and cancer. Current research reveals that tumors are not isolated masses but complex biological systems integrated with neural networks. They actively recruit nerve fibers through neurotrophin release, generate neurons from cancer stem cells, and establish functional synaptic-like connections with the nervous system. The sympathetic branch consistently exploits this neuro-integration to promote oncogenesis across multiple cancer types. Norepinephrine and epinephrine released from its terminals enhance tumor cell proliferation, angiogenesis, and metastatic dissemination while suppressing anti-tumor immunity. β2-adrenergic receptor signaling, via the activation of cAMP-PKA pathways, serves as a key mediator of these effects. In contrast, the parasympathetic system displays a more nuanced, organ-specific role. Cholinergic signaling through muscarinic receptors can accelerate progression in gastric, pancreatic, and colorectal cancers by promoting stemness and proliferation. Conversely, parasympathetic activity may suppress tumor growth and metastasis in contexts like breast cancer and certain gastrointestinal malignancies, primarily through immunomodulatory mechanisms. This neurobiological framework reconceptualizes tumors as “neuro-integrated organs” that actively shape and exploit host neural architecture. Understanding this interplay repositions the nervous system from a passive bystander to a central and ultimately targetable regulator of oncogenesis. This review provides a narrative synthesis of current literature examining the interplay between the autonomic nervous system and cancer. Our approach involved a targeted survey of recent experimental and clinical studies covering key domains such as tumor innervation, sympathetic and parasympathetic regulation, adrenergic and cholinergic signaling, and neuroimmune interactions. Emphasis was placed on extracting mechanistic insights and identifying translational opportunities for therapeutic modulation. The resulting synthesis provides a conceptual framework for viewing cancer as a neurobiologically integrated disease process.