Objective: The purpose of this study is to explore the role and mechanism of S100A4 nuclear localization in pancreatic cancer metastasis. Method: 1. The expression of S100A4 in the pancreatic cancer cells, especially in the nucleus, was quantified by immunohistochemistry and HALO digital pathology precision analysis platform using tissue microarray of the progression of pancreatic cancer, and the relationship between each detection index and various clinical parameters and survival time was statistically analyzed. 2. Through molecular structure information analysis, plasmid design and transfection to construct different grouping cell research models of gene regulation; Nuclear and cytoplasmic extraction, co-immunoprecipitation (Co-IP), western blot, wound healing assay, transwell assay and CUT&Tag assay were used to study the role and mechanism of S100A4 nuclear localization in pancreatic cancer metastasis. Results: 1. Not only the high expression of S100A4 but also the nuclear expression of S100A4 was positively correlated with the T and N stages and poor prognosis of pancreatic cancer. 2. The nuclear localization of S100A4 in pancreatic cancer cells is regulated by SUMOylation. The specific mechanism is that UBC9 mediates the binding of K22 and K96 of S100A4 to SUMO1 and deSUMOylation through SENP1, which dynamically balance the SUMOylation level of S100A4 in pancreatic cancer cells; Regulating SUMOylation of S100A4 can alter the metastatic ability of pancreatic cancer cells in vitro; The results of CUT&Tag sequencing confirmed that S100A4 nuclear localization was involved in the regulation of gene network related to tumor metastasis. Conclusion: Nuclear expression of S100A4 quantitative indicates poor prognosis of pancreatic cancer, is expected to become the important basis of clinical decision making. Finding a way to block or inhibit the nuclear localization of S100A4 may be a new way to inhibit the metastasis of pancreatic cancer, especially the early metastasis, and improve the prognosis of pancreatic cancer patients.