Interactions Between the Nervous System and PDAC Progression: Regulatory Mechanisms and Therapeutic Implications

Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human cancers. This review highlights recent advances in understanding how central and peripheral neural activity shapes PDAC, with a focus on signaling pathways, cellular mediators, and emerging research directions. Sympathetic fibers foster a pro-tumorigenic microenvironment through catecholamine release, while parasympathetic inputs can exert context-dependent inhibitory effects. Sensory pathways, Schwann cells, and neurotrophic factors further remodel the tumor niche, enabling invasion and immune escape. At the systemic level, stress responses amplify this neuro–tumor crosstalk, accelerating disease progression. Therapeutically, strategies that disrupt neural cues-such as β-blockers, Trk inhibitors, or selective denervation-are showing promise in preclinical and early clinical studies. By revealing how PDAC exploits neural mechanisms, this work underscores the potential of neuro-targeted therapies to complement conventional approaches and reshape the future of pancreatic cancer treatment. • Neuro–tumor crosstalk is a key driver of PDAC progression, integrating central and peripheral neural inputs with tumor biology. • Sympathetic signaling promotes a pro-tumorigenic microenvironment through catecholamine-mediated modulation of immune and stromal cells. • Parasympathetic and sensory pathways exert context-dependent roles, influencing tumor growth, invasion, and pain. • Schwann cells and neurotrophic factors reshape the tumor niche, enabling perineural invasion and immune evasion. • Systemic stress responses amplify neural influences on PDAC, linking psychological and physiological stress to disease progression. • Neuro-targeted therapies—such as β-blockers, Trk inhibitors, and selective denervation—show translational promise in preclinical and early clinical models. • Understanding neural regulation offers new therapeutic avenues to complement conventional PDAC treatments and improve patient outcomes.