Neuro-tumor-immune crosstalk in pancreatic cancer: Mechanisms and therapeutic insights

The nervous system functions as a central regulatory network that maintains physiological homeostasis through the coordinated actions of the central and peripheral nervous systems. The emergence of cancer neuroscience has unveiled novel mechanisms underlying bidirectional regulation among the nervous system, tumor cells, and the immune system. This review focuses on pancreatic cancer, often referred to as the "king of cancers," a malignancy characterized by aggressive behavior, early perineural invasion, and dismal prognosis. We systematically analyze the interactions within the neuro-tumor-immune microenvironment. On one hand, the peripheral and central nervous systems promote neurotropic migration of cancer cells and the formation of a tumor immunosuppressive microenvironment through neurotransmitters, neurotrophic factors, and synaptic remodeling. On the other hand, cancer cells and the immune microenvironment reshape neural structures, exacerbating immune evasion and malignant progression. Furthermore, this review integrates fundamental mechanisms with translational and clinical research, and proposes neuroscience-guided precision therapeutic strategies, including the development of neural invasion-related biomarkers and the targeting of key nodes within neuro-tumor-immune interactions. Together, these approaches add a new dimension to overcoming therapeutic bottlenecks in pancreatic cancer and facilitate the translation of mechanistic insights into clinical applications.