Decoding neuro-tumor interactions in pancreatic cancer: mechanisms, immunosuppressive networks and therapeutic opportunities

Abstract Pancreatic cancer is one of the most lethal digestive system malignancies worldwide, characterized by insidious onset, limited early detection approaches and extremely poor long-term prognosis. It comprises multiple histological subtypes, among which pancreatic ductal adenocarcinoma (PDAC) represents the most prevalent exocrine neoplasm and accounts for the vast majority of all pancreatic cancer cases. Perineural invasion (PNI) stands as one of the defining biological hallmarks of PDAC. Detected in 80%–100% of PDAC patients, PNI serves as an independent adverse prognostic factor that drives local recurrence, distant metastasis, and resistance to both chemotherapy and immunotherapy. Historically regarded as a passive route for tumor dissemination, PNI is now recognized as a complex, multicellular process involving bidirectional crosstalk between cancer cells, nerve fibers, stromal cells, and immune components within the tumor microenvironment. This review dissects the molecular mechanisms underlying neuro-tumor interactions and proposes a unified four-stage mechanistic model of PNI, encompassing mutual chemotaxis between tumors and nerves, adhesion and invasion at the tumor-nerve interface, extracellular matrix remodeling, and neural plasticity alterations. Notably, we define the perineural invasion microenvironment as a neuro-immune privileged sanctuary, and delineate its multicellular composition and pathological consequences based on current research advances. Furthermore, we summarize potential therapeutic strategies targeting the neuro-immune-tumor axis and ongoing clinical trials, discuss key translational challenges, and highlight the transformative applications of multi-omics technologies and artificial intelligence in PNI diagnosis, mechanistic discovery, and therapeutic optimization. This work provides a comprehensive theoretical framework for understanding PNI mechanisms and guides future translational research and precision therapy development for pancreatic cancer.