2. Academic Validation
  3. Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in glioblastoma

Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in glioblastoma

  • Cell Death Dis. 2025 Dec 10. doi: 10.1038/s41419-025-08288-3.
Cheng Miao 1 2,  Zehua Ding 3,  Jiaxing Wu 3,  Qi An 3,  Ya Shu 4,  Haifeng Jiang 3,  Panpan Gao 3,  Ruoqiao Chen 5,  Xiao Qian Chen 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongi University, Shanghai, China. [email protected].
  • 2 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Diseases, Ministry of Education; Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 3 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Diseases, Ministry of Education; Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Pharmacy, The First Affiliated Hospital of Yangtze University, Jingzhou, China.
  • 5 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA. [email protected].
  • 6 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Diseases, Ministry of Education; Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China. [email protected].
PMID: 41365876 DOI: 10.1038/s41419-025-08288-3
Abstract

The standard care of glioblastomas (GBM) confers limited survival benefit for patients due to the rapid tumor recurrence. Targeting tumor-associated macrophages/microglia via colony-stimulating factor 1 receptor (CSF-1R) inhibition is potentially effective in suppressing GBM recurrence. However, clinical trials of CSF-1R inhibitors failed to achieve their goal due to GBM resistance to anti-CSF-1R therapy. Here, we identified and verified key resistance mechanisms of anti-CSF-1R therapy by translatome profiling-combined analyses. To solve above problem, we have established a highly stable and refractory mouse G422TN-GBM model, in which temozolomide (TMZ) is the most effective monotherapy but can only slightly extend animal survival. To identify effective resistance mechanism of anti-CSF1R therapy in GBM, we first apply the Translating ribosome affinity purification (TRAP) RNA-sequencing techniques in GBM tissues, which have previously used in neuroscience. TRAP-seq identified Oxidative Phosphorylation/glycolysis as anti-CSF1R therapy resistance mechanism, and it's combined with Cancer Therapeutics Response Portal (CTRP) identified piperlongumine (PL) or vorinostat (SAHA) as targeting drugs. PL or SAHA enhanced PLX3397 efficacy by reversing Oxidative Phosphorylation/glycolysis dysregulation in vitro and in vivo. The triple combination of PLX3397, TMZ, and PL/SAHA significantly improved survival in G422TN-GBM mice. In conclusion, targeting Oxidative Phosphorylation/glycolysis by PL or SAHA prominently improves therapeutic efficacy of PLX3397 + TMZ in GBM, which deserves priority for clinical trials. Our study also reveals that translatome profiling is efficient for uncovering drug-resistant targets.

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