Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages

Tumor-associated macrophages (TAMs) are important tumor-promoting cells. However, the mechanism underlying how tumor and its microenvironment reprogram these cells remains elusive. Here we report that lipids play a crucial role in TAM generation in tumor microenvironment. Macrophages from both human and murine tumor tissues are enriched with lipids as a result of increased lipid uptake by macrophages. TAMs expressed elevated levels of the scavenger receptor CD36, accumulated lipids, and used fatty acid oxidation (FAO) instead of glycolysis for energy. High levels of FAO promoted mitochondrial oxidative phosphorylation, production of reactive oxygen species, phosphorylation of JAK1 and dephosphorylation of SHP1, leading to STAT6 activation and transcription of genes regulating TAM generation and function. These processes were critical for TAM polarization and activity in vitro and in vivo. In summary, we describe a novel mechanism underlying lipid metabolism-initiated process that promotes the differentiation and function of the protumor TAMs in TME.