Acquisition of a lipid-laden phenotype by immune cells has been defined in infectious diseases and atherosclerosis but remains largely uncharacterized in cancer. Here, in breast cancer models, we found that neutrophils are induced to accumulate neutral lipids upon interaction with resident mesenchymal cells in the premetastatic lung. Lung mesenchymal cells elicit this process through repressing the adipose triglyceride lipase (ATGL) activity in neutrophils in prostaglandin E2-dependent and -independent manners. In vivo, neutrophil-specific deletion of genes encoding ATGL or ATGL inhibitory factors altered neutrophil lipid profiles and breast tumor lung metastasis in mice. Mechanistically, lipids stored in lung neutrophils are transported to metastatic tumor cells through a macropinocytosis–lysosome pathway, endowing tumor cells with augmented survival and proliferative capacities. Pharmacological inhibition of macropinocytosis significantly reduced metastatic colonization by breast tumor cells in vivo. Collectively, our work reveals that neutrophils serve as an energy reservoir to fuel breast cancer lung metastasis.

在感染性疾病和动脉粥样硬化中已经定义了通过免疫细胞获得带有脂质的表型，但是在癌症中仍然没有很多特征。在这里，在乳腺癌模型中，我们发现嗜中性粒细胞在与转移前肺中的间充质细胞相互作用时被诱导积累中性脂质。肺间充质细胞通过以前列腺素E2依赖性和非依赖性方式抑制嗜中性粒细胞中的甘油三酸酯脂肪酶（ATGL）活性来引发这一过程。在体内，中性粒细胞特异性编码ATGL或ATGL抑制因子的基因的缺失改变了小鼠中性粒细胞的脂质分布和乳腺肿瘤肺转移。从机理上讲，储存在肺中性粒细胞中的脂质通过巨胞饮-溶酶体途径被转移到转移性肿瘤细胞，使肿瘤细胞具有增强的生存能力和增殖能力。巨细胞增多症的药理学抑制作用显着降低了体内乳腺肿瘤细胞的转移定植。总的来说，我们的研究表明中性粒细胞是促进乳腺癌肺转移的能量库。