Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion

Nian Jiang, Bowen Xie, Wenwu Xiao, Ming Fan, Shanxiu Xu, Yixin Duan, Yamah Hamsafar, Angela C. Evans, Jie Huang, Weibing Zhou, Xuelei Lin, Ningrong Ye, Siyi Wanggou, Wen Chen, Di Jing, Ruben C. Fragoso, Brittany N. Dugger, Paul F. Wilson, Matthew A. Coleman, Shuli XiaXuejun Li, Lun Quan Sun, Arta M. Monjazeb, Aijun Wang, William J. Murphy, Hsing Jien Kung, Kit S. Lam, Hong Wu Chen, Jian Jian Li

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A−/−, CPT2−/−, ACAD9−/− cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.

Original languageEnglish
Article number1511
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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