Lung cancer cells upregulate stearoyl-CoA desaturase 1 in microglia by activating the STAT3 pathway to change microglial inflammatory response in lung-to-brain metastases.

Lung cancer brain metastases have been considered a terminal disease stage with limited treatment options. Many studies have shown that microglia as the resident macrophages in the brain form a major component of the brain immune system, and the lipid metabolism of macrophages in the tumor microenvironment could directly influence tumor progression. However, limited studies have explored the regulatory role of lipid metabolism on microglia in brain metastases. In this study, we found that lung cancer cells could promote microglia to express stearoyl-CoA desaturase 1 (SCD1) and accumulate lipid droplets. Increased activity of SCD1 in microglia reduced its response to inflammatory stimuli and promoted the proliferation of cancer cells. Notably, the treatment of tumor-bearing mice with an SCD1 inhibitor combined with an inhibitor of colony-stimulating factor 1 receptor (CSF1R) significantly reduced brain metastases. Mechanistically, we demonstrated that lung cancer cells activated the STAT3 signaling pathway in microglia leading to increased SCD1 expression. In conclusion, our findings indicate that lung cancer cells activate the microglial STAT3-SCD1-lipid metabolism-inflammatory response pathway in the brain tumor microenvironment and present a potential new strategy for treating brain metastases of lung cancer.