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

• Published in: Acta pharmaceutica Sinica. B 2023-12, Vol.13 (12), p.4733-4747
• Main Authors: Wang, Mingjin, Wang, Weida, You, Shen, Hou, Zhenyan, Ji, Ming, Xue, Nina, Du, Tingting, Chen, Xiaoguang, Jin, Jing
• Format: Article
• Language: English
• Subjects: Acetyl-CoA acetyltransferase 1; CXCL1; Glioblastoma; Lipid metabolism; Macrophages; Myeloid cells; Myeloid-derived suppressor cells; Original; Tumor microenvironment
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.09.005

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor 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 (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME. Myeloid-specific depletion of ACAT1, a vital mitochondrial enzyme, boosts tumor growth by expanding MDSCs, attributed to increasing secretion of CXCL1 by ACAT1-deficient Mφs. [Display omitted]