Central Carbon Metabolism Regulates Macrophage Antitumor Activity

Macrophages play a dual role in tumorigenesis depending on their polarization phenotype, with proinflammatory M1 macrophages mediating antitumor immunity via phagocytosis of tumor cells and immunosuppressive M2 macrophages supporting tumor growth. These different functions are regulated in part by the balance of stimulatory signals, such as Toll-like receptors (TLR), and inhibitory signals, including CD47, an antiphagocytic protein overexpressed by tumor cells. Liu and colleagues found that, whereas antibody blockade of CD47 was not sufficient to stimulate macrophage antitumor activity in a mouse model of pancreatic ductal adenocarcinoma (PDAC), treatment with CpG oligonucleotide, a TLR9 agonist, enhanced macrophage phagocytosis of PDAC cells and suppressed tumor growth in vivo. This antitumor response was mediated by CSF1R⁺ tumor-associated macrophages and was sufficient to overcome inhibitory CD47 expression by PDAC cells and other nonhematopoietic tumor cells. Mechanistically, CpG induced a rewiring of macrophage metabolism characterized by enhanced oxidative phosphorylation without polarization to the classic M1 or M2 phenotype. This unique metabolic state was required for CpG-mediated stimulation of macrophage antitumor activity and was dependent on increased fatty-acid oxidation (FAO) and a shift in the use of TCA cycle intermediates for de novo lipogenesis. Inhibition of the FAO enzyme carnitine palmitoyltransferase 1A or ATP citrate lyase, a key enzyme in fatty-acid biosynthesis, prevented the CpG-driven increase in macrophage oxygen consumption and abolished the ability of CpG-stimulated macrophages to phagocytose PDAC cells. These findings establish a critical role for macrophage central carbon metabolism in circumventing inhibitory immune checkpoint signals and suggest that targeted rewiring of the metabolic state in macrophages may potentiate antitumor responses.

Liu M, O'Connor RS, Trefely S, Graham K, Snyder NW, Beatty GL. Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47–mediated ‘don't-eat-me’ signal. Nat Immunol 2019 Jan 21 [Epub ahead of print].

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