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Pancreatic cancer is characterized by nerve invasion and a high mortality rate, and its pathological process depends on the complex interaction network between tumor and the nervous system. Based on the concept of “pancreatic cancer neuroecology”, this article analyzes the mechanism of action of peripheral motor nerve, sensory nerve, and central nerve in tumorigenesis, pain regulation, and cachexia formation and emphasizes the synergistic regulatory role of immune cells, Schwann cells, and extracellular matrix in the microenvironment of perineural invasion. At the same time, this article further elaborates on the metabolic interaction and chemotaxis between neuraxis and tumor, the effect on promoting chemotherapy resistance, and the dynamic relationship between neuroplasticity and tumor adaptability. In clinical practice, this article summarizes the key value of perineural invasion in prognostic evaluation, preoperative evaluation, and the selection of surgical strategy. In addition, this article reviews the basic research advances in the biomarkers and potential targets associated with perineural invasion in pancreatic cancer and points out the limitations of current model and transformation research. In the future, systematically analyzing the nerve-tumor-immune network and targeting its key nodes may provide multi-dimensional strategies and new breakthroughs for the precise intervention of pancreatic cancer, the reversal of drug resistance, and the relief of symptoms.
