Myeloid-derived suppressor cells (MDSCs) have become increasingly recognized as facilitators of tumor development. However, the role of MDSCs in papillary thyroid carcinoma (PTC) progression has not been clearly explored.We aimed to evaluate the levels as well as function of circulating MDSCs in PTC.The proportion of circulating PMN-MDSCs and M-MDSCs from patients with PTC or benign thyroid nodules and healthy controls was measured using flow cytometry. For immunosuppressive activity analysis, sorted circulating MDSCs were co-cultured with CD3/CD28-costimulated T lymphocytes and the proliferation of T cells was determined. PTC cell lines (TPC-1 and BC-PAP) were co-cultured with PMN-MDSCs, and the effects on cell migration, invasion, proliferation and apoptosis were evaluated. The differential expressed miRNAs and mRNAs and their function were also explored in TPC-1 cells cocultured with or without PMN-MDSCs.PMN-MDSCs were increased in the peripheral blood mononuclear cells (PBMC) of patients with PTC. Circulating PMN-MDSCs displayed strong T cell suppressive activity. PTC cells demonstrated enhanced invasive capabilities in vitro and in vivo when co-cultured with sorted PMN-MDSCs. PMN-MDSCs decreased expression of miR-486-3p and activated NF-κB2, a direct target of miR-486-3p. Rescue of miR-486-3p diminished the cell migration and invasion induced by PMN-MDSCs.Collectively, our work indicates that circulating PMN-MDSCs promote PTC progression. By suppressing miR-486-3p, PMN-MDSCs promote the activity of the NF-κB2 signaling pathway, resulting in accelerated invasion of PTC cells, which may provide new therapeutic strategies for treatment of thyroid cancer.