Semaglutide Reprograms Macrophages via the GLP-1R/PPARG/ACSL1 Pathway to Suppress Papillary Thyroid Carcinoma Growth.

CONTEXT: The use of glucagon-like peptide-1 receptor (GLP-1R) agonists such as semaglutide, a novel class of antidiabetic medications, has raised concerns about potential adverse effects, particularly a possible association with thyroid cancer (TC). OBJECTIVE: This study aims to evaluate whether semaglutide influences the progression of TC by modulating tumor-associated macrophages (TAMs). METHODS: Semaglutide was administered to human papillary thyroid carcinoma (PTC) xenograft mouse models, coculture systems consisting of human THP-1 macrophage cells and PTC cells, and primary murine peritoneal macrophages. Assessments included tumor size, M1/M2 macrophage ratio, PTC cell proliferation, and polarization marker expression. RESULTS: Semaglutide did not significantly impact the proliferation of PTC cells but reduced tumor size and inhibited the proliferation of PTC cells in coculture systems. It increased M1 and decreased M2 macrophages, reprogramming polarization by downregulating PPARG expression. Cotreatment with semaglutide and a PPARG agonist in the coculture system confirmed the upregulation of downstream genes RSAD2, ACSL1, and PLA2G7. Silencing ACSL1 inhibited lipid accumulation in THP-1 cells and promoted polarization toward the M2 macrophage phenotype. CONCLUSION: Semaglutide modulates macrophage lipid metabolism through the GLP-1R/PPARG/ACSL1 signaling pathway. This modulation promotes the conversion of TAMs to the M1 macrophage phenotype, enhancing their anticancer activity. These findings suggest that semaglutide may improve therapeutic strategies, reduce unnecessary thyroid nodule screenings, and broaden its clinical applications.