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

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.

Glioblastoma Stem-Like Cells (GSCs) with Mesenchymal Signature: Lipid Profiles of Mobile Lipids Obtained with MRS before and after Radio/Chemical Treatments

“…On the other hand, etomoxir, a widely used small-molecule inhibitor of FAO through its irreversible inhibitory effects on CPT1a, induced a cytotoxic effect in both MES lines, more evident in line #74, associated to a decrease in lipid content measured as cross peak A, as expected. This is in agreement with a recent study, in which lowered glycolysis and a remarkably low level of cytoplasmic lipids were detected in radioresistant glioblastoma cells after FAO inhibition by etomoxir [ 72 ]. The level of unsaturation (cross-peak ratios B/A, M/A, and P/A) seems not to be affected by either kind of treatments.…”

COVID‐19 metabolism: Mechanisms and therapeutic targets

“… 100 Enzymes from both fatty acid beta‐oxidation (acyl‐CoA dehydrogenases, ACADM and ACAD9) and lipogenesis (ATP citrate lyase, ACLY) were found to interact with viral proteins. 138 , 139 , 140 Strikingly, Nsp7 seems to be a potent regulator of lipid metabolism as it interacted with four different enzymes from this pathway. Among binding partners of Nsp7, acyl‐CoA synthetase long‐chain family member 3 (ACSL3) converts free long‐chain fatty acids into fatty acyl‐CoA esters to support lipid biosynthesis 141 (Figure 4F ).…”

Deciphering the Biological Effects of Radiotherapy in Cancer Cells

“…Recently, fatty acids have been found to be an alternative pivotal resource for energy, and thus, contribute to radiation-induced resistance by facilitating the oxidation of mitochondrial fatty acids (FAO) [ 47 , 48 , 49 ]. Notably, fatty acid metabolism can also enhance CD47-mediated anti-phagocytosis in glioblastoma multiforme.…”

“…Notably, fatty acid metabolism can also enhance CD47-mediated anti-phagocytosis in glioblastoma multiforme. Mechanistically, acetyl-CoA, which is one of the main metabolites of FAO, upregulates the expression of CD47 by acetylating RelA K310 [ 47 ]. It is also notable that the crosstalk between lipid droplets and iron metabolism makes cancer cells more radioresistant [ 50 ].…”