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Lipid metabolism in cancer cells and tumor-associated stromal cells was recently identified to contribute to disease progression particularly in response to changes in tumor microenvironment such as acidosis and hypoxia.New molecular mechanisms driving lipid metabolism in various cancers were elicited through genetic silencing, pharmacological inhibition of key metabolic enzymes, including those involved in fatty acid oxidation and synthesis, and modulation of diet composition.To proliferate, metastasize, or resist stress conditions imposed by the microenvironment, many cancer cells rely on fatty acid β-oxidation to generate acetyl-CoA and fuel the TCA cycle, and on fatty acid synthesis to produce building blocks. These processes are fine-tuned through regulation of acetyl-CoA carboxylases expression and activity. Stromal cells including lymphocytes, (lymphatic) endothelial cells and adipocytes also participate through either fatty acid transfer or lipid-based signaling to cancer disease progression. Altogether, these data identify critical nodes in the orchestration of lipid metabolism in cancer that may facilitate the design of synthetic-lethal treatments.