Objective：To explore the role and mechanism of S100A4 nuclear localization in pancreatic cancer（PC）metastasis. Methods：The expression of S100A4 in the PC cells，especially in the nucleus，was quantified by immunohistochemistry and HALO digital pathology precision analysis platform using the tissue microarray of PC. Statistical analysis was conducted to assess the correlations of each detection index with various clinical parameters and survival rates. Molecular structure informatic analysis， plasmid construction，and transfection were used to create different gene regulation cell research models. Techniques such as nuclear and cytoplasmic extraction，co-immunoprecipitation，Western blotting，wound healing assay，transwell assay，and cleavage under targets and tagmentation（CUT&Tag）assay were used to study the role and mechanism of S100A4 nuclear localization in PC metastasis. Results：High expression and the nuclear localization of S100A4 were positively correlated with T and N stages and poor prognosis in PC. The nuclear localization of S100A4 in PC cells was regulated by small ubiquitin-related modifier（SUMO） modification. Ubiquitin conjugating enzyme 9 mediated the binding of S100A4 to SUMO1 at K22 and K96 sites in PC cells，and deSUMOylation was achieved by sentrin-specific protease 1，dynamically balancing the SUMOylation level of S100A4. Regulating the SUMOylation of the S100A4 protein altered the metastatic ability of PC 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：S100A4 nuclear localization may indicate poor prognosis in PC and serve as a crucial basis for clinical decision making. Identifying methods to block or inhibit S100A4 nuclear localization may provide a new approach to suppress PC metastasis，especially the early metastasis， and improve the prognosis of PC patients.