Cedrol impedes lung cancer metastasis by reducing tumor-associated macrophage polarization mediated by MYC-driven aerobic glycolysis

The occurrence of tumor metastasis is associated with the phenotype of tumor-associated macrophages (TAMs). Within the tumor microenvironment, TAMs undergo metabolic reprogramming. Aerobic glycolysis contributes to TAM polarization into an M2-like phenotype. Cedrol is a component extracted from herbal medicines. Anti-cancer activities of cedrol have been reported, however, its effect on the metabolic reprogramming and pro-metastatic ability of TAMs remains unclear. Here, we found that cedrol reduced THP-1-derived macrophage polarization into M2-like phenotypes. Cedrol impaired the promoting effects of TAMs on the migration and invasion of lung cancer cells. Tumor metastasis in C57BL/6 mice was reduced following cedrol treatment, accompanied by decreases in M2-like TAMs in the lung tissues. Cedrol treatment decreased glucose consumption and lactate production and downregulated glycolysis-associated gene expression. A glycolytic inhibitor (2-DG) was utilized to confirm that suppression of glycolysis in TAMs limited the metastasis of lung cancer cells. MYC was identified as a downregulated gene in cedrol-treated TAMs based on the mRNA sequencing analysis. MYC overexpression could reverse the effects of cedrol on TAMs. Cedrol treatment reduced MYC expression at least partly via the PI3K-Akt pathway. These findings suggest that cedrol exerts anti-tumor effects by inhibiting TAM polarization into an M2-like phenotype by modulating MYC-mediated aerobic glycolysis, indicating cedrol as a potential drug for lung cancer treatment.