Neural-immune-cancer crosstalk in pancreatic cancer: mechanisms and clinical translation

Pancreatic cancer remains a persistently high mortality rate, with limited efficacy through traditional therapies, necessitating exploration of its pathogenesis from a new biological perspective. The tumor microenvironment plays a decisive role in the malignant progression of pancreatic cancer, and the nervous system, as a key component of the microenvironment, has an active and bidirectional interaction with tumor cells, known as the "neuro-tumor interaction." Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is highly rich in neural components. The neuro-tumor interaction not only drives the unique neural infiltration of PDAC but also profoundly affects tumor proliferation, invasion, metastasis, immune escape, and pain perception. Recent studies have revealed that tumor cells, Schwann cells, cancer-associated fibroblasts, and immune cells form a "perineural niche" through neurotrophic factors, chemotactic axes, cell adhesion/extracellular matrix remodeling, and neurotransmitters, driving tripartite neural-immune-cancer interaction and providing targets for new therapeutic interventions. This review systematically summarized the key molecular and cellular mechanisms of neural-immune-cancer interactions in pancreatic cancer and specifically discussed several translational strategies, including neurotrophic factor blockade targeting NGF/TrkA and GDNF/RET, myeloid cell reprogramming targeting CXCR2/CXCL to improve T cell infiltration, and potential combination strategies that combine neuromodulatory drugs (e.g., β-blockers or CRGP antagonists) with immune checkpoint inhibitors. These strategies have shown feasibility in preclinical studies or PDAC models and warrant further validation in stratified clinical trials.