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.

中文翻译：

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肿瘤相关巨噬细胞的分化和活化需要增强的脂质积累和代谢。

肿瘤相关巨噬细胞 (TAM) 是重要的促肿瘤细胞。然而，肿瘤及其微环境如何重编程这些细胞的机制仍然难以捉摸。在这里，我们报告脂质在肿瘤微环境中的 TAM 生成中起着至关重要的作用。由于巨噬细胞对脂质的摄取增加，来自人和鼠肿瘤组织的巨噬细胞富含脂质。TAMs 表达水平升高的清道夫受体 CD36，积累脂质，并使用脂肪酸氧化 (FAO) 而不是糖酵解来获取能量。高水平的FAO促进线粒体氧化磷酸化、活性氧的产生、JAK1的磷酸化和SHP1的去磷酸化，导致STAT6激活和调节TAM生成和功能的基因转录。这些过程对于体外和体内的 TAM 极化和活性至关重要。总之，我们描述了一种促进 TME 中原瘤 TAM 分化和功能的脂质代谢启动过程的新机制。