ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppres-sive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived sup-pressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (M4). Overall, our findings demonstrate that ACAT1 could serve as a prom-ising drug target for GBM by regulating the function of MDSCs in the TME. (c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs) play a crucial role in suppressing antitumor immunity in this environment. Lipometabolism is closely related to the function of myeloid cells. The study shows that acetyl-CoA acetyltransferase 1 (ACAT1), a key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the infiltrated MDSCs in GBM patients. Depletion of ACAT1 in mice resulted in the accumulation of MDSCs and increased tumor progression, likely due to elevated secretion of C-X-C motif ligand 1 (CXCL1) by macrophages (M4). These findings suggest that ACAT1 could be a promising drug target for GBM by regulating the function of MDSCs in the TME.