Abstract: Objective: To investigate the molecular mechanisms of SOX17 on regulating macrophage M1 polarization in thyroid cancer (TC) metastasis. Methods: The differential expression of SOX17 in TC patients and healthy controls was analyzed through GEPIA2 database.The expression levels of SOX17 in TC and paired adjacent normal tissues were detected by Western blotting and IHC.Then, it was further assessed in different TC cell lines (TPC-1, KTC-1, and SW579).TPC-1 cells were transfected with SOX17 overexpression lentiviral vectors, and macrophage M1 polarization was induced.The macrophage polarization was detected by flow cytometry, and the effects of SOX17 overexpression on the migration, invasion and epithelial-mesenchymal transition (EMT) of TPC-1 cells were evaluated by scratch assay and Transwell assay. Results: SOX17 expression was significantly lower in TC tissues and cell lines than in the paired adjacent noncancerous tissues and the normal thyroid follicular epithelial cell in line when compared to adjacent normal tissues(P < 0.05).SOX17 overexpression significantly induced macrophage M1 polarization and inhibited M2 polarization, which expressed with the upregulation of M1 marker CD86 and downregulation of M2 marker CD206 (P < 0.01).Furthermore, SOX17 overexpression significantly suppressed the EMT process in TPC-1 cells, which expressed with the decreased expression of Vimentin and N-cadherin and the increased expression of E-cadherin (P < 0.01).The migration and invasion abilities of TPC-1 cells were significantly reduced in the SOX17 overexpression group (P < 0.01). Conclusions: SOX17 may suppress TC metastasis by regulating macrophage M1 polarization, inhibiting tumor cell migration, invasion and EMT.