Artesunate Suppresses the Migration and Invasion of Thyroid Cancer Cells via Upregulating <scp>PTEN</scp> to Block <scp>M2</scp> Polarization of Tumor‐Associated Macrophages

Immunotherapy holds promise for thyroid cancer (TC) treatment. In the context of our previous findings that artesunate (ART) could inhibit the migration and invasion of TC cells through phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), this study was engineered to investigate whether ART regulates the tumor microenvironment in TC. THP-1 cells were differentiated into M0 macrophages by the induction of 100 ng/mL of phorbol 12-myristate 13-acetate and transfected as needed. M0 macrophages were treated with different concentrations of ART (10 and 20 μM) for 24 h. The co-culture of macrophages and TC cells was conducted. Flow cytometry and enzyme-linked immunosorbent assay were used to identify M2 macrophages. The viability, migration, and invasion of TC cells were detected by cell counting kit-8, wound healing, and transwell assays. The mRNA or protein expressions of examined genes were measured by quantitative real-time polymerase chain reaction or Western blot. In co-cultured macrophages, protein expressions of CD206, CD163, and Arginase-1, as well as the secretion of IL-10 and CCL18, were promoted, but phosphatase and tensin homolog (PTEN) mRNA expression was inhibited, which were reversed by different concentrations of ART. In the co-culture system, 20 μM of ART downregulated mRNA expressions of CD206, CD163, and Arginase-1 in macrophages and diminished viability, migration, invasion, as well as ratios of p-PI3K/PI3K and p-Akt/Akt in TC cells, which were offset by PTEN deletion in macrophages. Collectively, ART suppresses the migration and invasion of TC cells via inhibiting the PI3K/Akt pathway by PTEN upregulation-blocked M2 polarization of tumor-associated macrophages.