Autonomic neural reprogramming in pancreatic ductal adenocarcinoma: Putative neurotumoral circuits linking perineural invasion to metastatic progression

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal gastrointestinal malignancy characterized by dense neural innervation and a pronounced tendency for perineural infiltration, pathological features closely associated with poor prognosis and metastatic spread.Recent studies support a model of PDAC as a neurotropic malignant tumor potentially associated with a self-reinforcing autonomic-neural-tumor network-in which sympathetic components, tumor cells, and stromal fibroblasts form an integrated neuro-oncologic network that may contribute to tumor invasiveness, microenvironment adaptation, and metastatic potential.However, evidence for spontaneous distant metastasis and clinically meaningful therapeutic benefit remains limited.This narrative review aims to examine the neuro-oncologic interface in PDAC, focusing on the sympathetic nerve-cancer associated fibroblasts feedback loop model and the PIEZO1-YAP1 mechanotransduction axis, and to discuss how these pathways may contribute to perineural invasion and systemic dissemination, thereby highlighting a potential novel therapeutic strategy.