Fatty Acid Oxidation Fuels Glioblastoma Radioresistance with CD47-mediated Immune Evasion

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Mar 22

PMID 35314680

Authors

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 Xia

Xuejun Li

Lun-Quan Sun

Arta M Monjazeb

Aijun Wang

William J Murphy

Hsing-Jien Kung

Kit S Lam

Hong-Wu Chen

Jian Jian Li

Affiliations

Soon will be listed here.

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.

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