FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo . Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer. Graphic Abstract Highlights Unlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages. Unsaturated fatty acids activate the FABP4/CEBPα axis for neutral lipid biosynthesis in macrophages Deficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophages FABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis