2. Academic Validation
  3. Inhibition of ICAM1 diminishes stemness and enhances antitumor immunity in glioblastoma via β-catenin/PD-L1 signaling

Inhibition of ICAM1 diminishes stemness and enhances antitumor immunity in glioblastoma via β-catenin/PD-L1 signaling

  • Nat Commun. 2025 Sep 30;16(1):8642. doi: 10.1038/s41467-025-63796-2.
Meixia Guo # 1 2,  Zheng Yuan # 1 2,  Xiong Jin # 1 2 3,  Xinyu Li 1 2,  Yilin Deng 1 2,  Shuchang Zhou 1 2,  Rui Niu 1 2,  Joonbeom Bae 4,  Jong Bae Park 5,  Bingyang Shi 6 7 8,  Jinlong Yin 9 10
Affiliations

Affiliations

  • 1 Henan-Macquarie University Joint Centre for Biomedical Innovations, School of Life Sciences, Henan University, Kaifeng, Henan, China.
  • 2 Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan, China.
  • 3 School of Pharmacy, Henan University, Kaifeng, Henan, China.
  • 4 Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
  • 5 Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
  • 6 Henan-Macquarie University Joint Centre for Biomedical Innovations, School of Life Sciences, Henan University, Kaifeng, Henan, China. bs@henu.edu.cn.
  • 7 Faculty of Medicine & Health Sciences, Macquarie University, Sydney, NSW, Australia. bs@henu.edu.cn.
  • 8 School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia. bs@henu.edu.cn.
  • 9 Henan-Macquarie University Joint Centre for Biomedical Innovations, School of Life Sciences, Henan University, Kaifeng, Henan, China. jlyin@henu.edu.cn.
  • 10 Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan, China. jlyin@henu.edu.cn.
  • # Contributed equally.
PMID: 41028719 DOI: 10.1038/s41467-025-63796-2
Abstract

Glioblastoma (GBM) stem cells (GSCs) are pivotal in tumor initiation, recurrence, and therapeutic resistance, underscoring their critical role in the complex pathology of GBM. Despite their recognized importance, the mechanisms by which GSCs facilitate immune evasion, especially in emerging immunotherapies, remain incompletely understood. Here, we identify intercellular adhesion molecule 1 (ICAM1) as a key regulator of GSC stemness and tumorigenicity, promoting an immunosuppressive microenvironment via β-catenin/PD-L1 signaling. Mechanistically, ICAM1 interacts with ZNRF3, leading to its autoubiquitination and clearance, stabilizing LRP6, and activating β-catenin signaling, which upregulates PD-L1 expression. Combined treatment with anti-ICAM1 and anti-PD-1 antibodies results in the most effective tumor inhibition and significantly extends survival in ICAM1-overexpressing GBM models. CyTOF and flow cytometry analyses reveal that ICAM1 overexpression reduces cytotoxic CD8+ T cell populations via PD-L1/PD-1 interactions, reversible by PD-1 blockade. Our findings highlight the co-targeting of ICAM1 and PD-1 as a promising strategy against immune evasion in GBM.

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