Nat Commun. 2018 Jul 3;9(1):2574. doi: 10.1038/s41467-018-04999-8.
Xiang W1, Shi R1, Kang X1, Zhang X2, Chen P3, Zhang L1, Hou A1, Wang R1, Zhao Y1, Zhao K1, Liu Y1, Ma Y1, Luo H1, Shang S1, Zhang J4, He F1, Yu S2, Gan L1, Shi C5, Li Y6, Yang W7, Liang H8, Miao H9.
Abstract
Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages (TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor-dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy.
