Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA.
Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
Nat Commun. 2022 Mar 21;13(1):1511. doi: 10.1038/s41467-022-29137-3.
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.
多形性胶质母细胞瘤（GBM）仍然是放射治疗的最大挑战，诊断后仅有 25%的患者能存活 1 年。在这里，我们揭示了在预后不良的复发性 GBM 患者中，线粒体脂肪酸氧化（FAO）酶（CPT1A、CPT2 和 ACAD9）和免疫检查点 CD47 的共增强是主要的。糖酵解到 FAO 的代谢重编程与放射性耐药 GBM 细胞中的 CD47 抗吞噬作用以及在同基因小鼠中放射后重新生长的 GBM 有关。CPT1 抑制剂 etomoxir 或 CRISPR 生成的 CPT1A、CPT2、ACAD9 细胞抑制 FAO 表明，FAO 衍生的乙酰辅酶 A 通过 NF-κB/RelA 乙酰化上调 CD47 转录。阻断 FAO 会损害肿瘤生长并降低 CD47 抗吞噬作用。etomoxir 联合抗 CD47 抗体协同增强巨噬细胞吞噬作用，控制重新生长的肿瘤的放射治疗。这些结果表明，增强的脂肪酸代谢通过 CD47 介导的免疫逃避促进 GBM 的侵袭性生长。FAO-CD47 轴可能成为通过消除 GBM 放射免疫治疗中具有抗辐射吞噬作用的肿瘤细胞来改善 GBM 控制的靶点。
