Macrophages adapt to glucose deprivation by partly reversing an important metabolic pathway

What is it about?

How do cells rewire their metabolism when the local supply with important nutrients is limited? In diseases, such as cancer, cells may be exposed to very harsh conditions, due to an insufficient supply with nutrients from the bloodstream and high metabolic activity. This study shows that macrophages can flip a major metabolic pathway, glycolysis, to perform initial steps of the reverse pathway, gluconeogenesis, under glucose limitation. Macrophages are versatile immune cells which are reprogrammed by tumor cells to inhibit immune responses and attract blood vessels. The researchers show that this yet poorly understood metabolic pathway is activated in different subsets of macrophages upon starvation leading e.g. to the synthesis of important cellular building blocks from alternative sources. While under glucose deprivation central carbon metabolic pathways changed substantially, only subtle alterations in gene expression occurred. The study highlights the extensive metabolic flexibility of macrophages in changing microenvironments.

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Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Why is it important?

Cancer cells rely on supportive and protective actions of normal cells, like macrophages. Especially the anti-inflammatory properties of macrophages are of major interest, since their activity may hamper anti-tumor immune responses, and thus the efficacy of immune checkpoint inhibitor therapies. The metabolic microenvironment has been previously shown to compromise anti-tumor immune responses, however the role of glucose deprivation in shaping immune cell metabolism is still poorly understood. Partial gluconeogenesis has been shown to contribute to glycolytic pools in the absence of glucose in cancer cells, as previously discovered by the lab, and different normal cell types. However, this pathway has not been rigorously addressed in macrophages, which were among the cells with the highest expression levels of key enzymes of this pathway e.g. in the lung and lung cancer. While the researchers revealed an unexpected metabolic capacity of macrophages to reverse glycolysis, the role of this rather understudied pathway in health and disease is yet to be determined in future studies.

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