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

Meixia Guo, Zheng Yuan, Xiong Jin, Xinyu Li, Yilin Deng, Shuchang Zhou, Rui Niu, Joonbeom Bae, Jong Bae Park, Bingyang Shi () and Jinlong Yin ()
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Meixia Guo: Henan University
Zheng Yuan: Henan University
Xiong Jin: Henan University
Xinyu Li: Henan University
Yilin Deng: Henan University
Shuchang Zhou: Henan University
Rui Niu: Henan University
Joonbeom Bae: Korea University
Jong Bae Park: National Cancer Center
Bingyang Shi: Henan University
Jinlong Yin: Henan University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63796-2

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