2. Academic Validation
  3. Stress-induced pro-inflammatory glioblastoma stem cells secrete TNFAIP6 to enhance tumor growth and induce suppressive macrophages

Stress-induced pro-inflammatory glioblastoma stem cells secrete TNFAIP6 to enhance tumor growth and induce suppressive macrophages

  • Dev Cell. 2025 May 15:S1534-5807(25)00287-4. doi: 10.1016/j.devcel.2025.04.027.
Danling Gu 1,  Lang Hu 2,  Kailin Yang 3,  Wei Yuan 4,  Danyang Shan 5,  Jiancheng Gao 5,  Jiahuang Li 6,  Ryan C Gimple 7,  Deobrat Dixit 8,  Zhe Zhu 9,  Daqi Li 10,  Qiulian Wu 8,  Zhumei Shi 11,  Yingyi Wang 12,  Ningwei Zhao 13,  Kun Yang 14,  Junfei Shao 15,  Fan Lin 16,  Qianghu Wang 17,  Guangfu Jin 17,  Yun Chen 18,  Xu Qian 17,  Zhibin Hu 17,  Chaojun Li 17,  Nu Zhang 19,  Yongping You 12,  Jian Liu 20,  Qian Zhang 21,  Junxia Zhang 22,  Jeremy N Rich 23,  Xiuxing Wang 24
Affiliations

Affiliations

  • 1 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu, China; National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 2 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 3 Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 4 Department of Pathology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng 224005, Jiangsu, China.
  • 5 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 6 School of Biopharmacy, China Pharmaceutical University, Jiangsu 211198, China.
  • 7 Department of Medicine, Washington University School of Medicine, Washington University in St Louis, St. Louis, MO 63110, USA.
  • 8 Department of Neurology, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA 15213, USA.
  • 9 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 10 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China; Department of Neurology, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA 15213, USA.
  • 11 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 12 Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 13 China Exposomics Institute, 781 Cai Lun Road, Shanghai 200120, China.
  • 14 Department of Neurosurgery, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu, China.
  • 15 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu, China.
  • 16 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 17 Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 18 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 19 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong Translational Medicine Innovation Platform, Guangzhou 510080, Guangdong, China.
  • 20 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China. Electronic address: liujian623@njucm.edu.cn.
  • 21 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China. Electronic address: zhangqian01@njmu.edu.cn.
  • 22 Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China. Electronic address: zjx232@njmu.edu.cn.
  • 23 Department of Neurology, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA 15213, USA. Electronic address: drjeremyrich@gmail.com.
  • 24 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu, China; National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, Jiangsu, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China; Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu, China. Electronic address: drxiuxingwang@163.com.
PMID: 40403724 DOI: 10.1016/j.devcel.2025.04.027
Abstract

Glioblastoma (GBM) is the most aggressive primary intracranial tumor, with glioblastoma stem cells (GSCs) enforcing the intratumoral hierarchy. The inflammatory microenvironment influences tumor development at varying stages, while the underlying mechanism of GSCs facing pro-inflammatory stress remains unclear. Here, we show that, in human GBM, pro-inflammatory stress from pro-inflammatory macrophages (pTAMs) maintains GSC proliferation and self-renewal. Tumor necrosis factor alpha-induced protein 6 (TNFAIP6), as a responder in patient-derived GSCs to pro-inflammatory stress tumor necrosis factor alpha (TNF-α) from human pTAMs, promotes tumor growth through binding epidermal growth factor (EGF) and prolonging EGF receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling activation. Meanwhile, pro-inflammatory stress-induced patient-derived GSCs secrete TNFAIP6 to transform macrophage phenotype from pTAMs to inflammatory-suppressive macrophages (sTAMs). Collectively, pharmacological or genetic disruption of TNFAIP6 autocrine and paracrine communication between patient-derived GSCs and TAMs inhibited GSC proliferation and self-renewal in vitro and in patient-derived xenograft tumor-bearing mice, suggesting that TNFAIP6 is an effective target for GBM therapy.

Keywords

glioblastoma; glioblastoma stem cells; pro-inflammatory stress; tumor necrosis factor alpha-induced protein 6; tumor-associated macrophage.

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