Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Herein, we find that the scavenger receptor CD36 is upregulated in metastasis-associated macrophages (MAMs) and deletion of CD36 in MAMs attenuates liver metastasis in mice. MAMs contain more lipid droplets and have the unique capability in engulfing tumor cell-derived long-chain fatty acids, which are carried by extracellular vesicles. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. Collectively, our findings uncover a mechanism by which tumor cells metabolically interact with macrophages in TME, and suggest a therapeutic potential of targeting CD36 as immunotherapy for liver metastasis.

Metabolic reprogramming is a new hallmark of cancer but it remains poorly defined in hepatocellular carcinogenesis (HCC). The fatty acid receptor CD36 is associated with both lipid and glucose metabolism in the liver. However, the role of CD36 in metabolic reprogramming in the progression of HCC still remains to be elucidated. In the present study, we found that CD36 is highly expressed in human HCC as compared with non-tumor hepatic tissue. CD36 overexpression promoted the proliferation, migration, invasion, and in vivo tumor growth of HCC cells, whereas silencing CD36 had the opposite effects. By analysis of cell metabolic phenotype, CD36 expression showed a positive association with extracellular acidification rate, a measure of glycolysis, instead of oxygen consumption rate. Further experiments verified that overexpression of CD36 resulted in increased glycolysis flux and lactic acid production. Mechanistically, CD36 induced mTOR-mediated oncogenic glycolysis via activation of Src/PI3K/AKT signaling axis. Pretreatment of HCC cells with PI3K/AKT/mTOR inhibitors largely blocked the tumor-promoting effect of CD36. Our findings suggest that CD36 exerts a stimulatory effect on HCC growth and metastasis, through mediating aerobic glycolysis by the Src/PI3K/AKT/mTOR signaling pathway.

Atherosclerosis is the key component of most cardiovascular diseases, including stroke and myocardial infarction.1–3 An inflamed endothelium recruits inflammatory cells, such as monocytes, via the expression of various mediators and chemokines.4–6 This, in addition to the accumulation of cholesterol and smooth muscle cells (SMCs) in the intima, leads to the transformation of monocytes into foam cells, which consume dead cells and lipids.7–9 The atherogenic process involves multiple cell types, that is, endothelial cells (ECs),10 SMCs,11 immune cells,12 and stem/progenitor cells,13 in which levels of both intracellular and extracellular reactive oxygen and nitrogen species play a fundamental role in vascular cell homoeostasis and eventually affects the development of atherosclerosis.14 Fine-tuning of cellular redox status is a prerequisite for the well-being of vascular system. Although too much oxidative stress can be detrimental, some basal levels are crucial for proper cell signaling. Recently, a number of publications in ATVB and other journals have demonstrated substantial progress in research into oxidative stress vascular disease, especially atherosclerosis.14–17 In the present article, we highlight these updated publications, providing insights into the mechanisms of reactive oxygen species (ROS) generation in pathophysiological conditions of the vessel wall, and the contribution of redox imbalance to lesion formation via influencing vascular cell (dys)functions. Oxidative stress is defined as a cellular condition where the damaging effect of oxidant is greater than the beneficial effect of antioxidants. Major oxidants are based on O2 molecules, which are taken in during respiration, with higher reactivity than molecular O2, and are known as ROS.14 ROS are, thus, broadly defined as oxygen-containing chemical species with higher reactive properties. Major ROS include superoxide (O2·−) and hydroxyl (HO·) free radicals, as well as nonradical …

Yun Li, Ping Yang, Lei Zhao, Yao Chen, Xiaoyu Zhang, Shu Zeng, Li Wei, Zac Varghese, John F. Moorhead, Yaxi Chen, Xiong Z. Ruan