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

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 the context of emerging immunotherapies, remain incompletely understood. Here, we identify the role of intercellular adhesion molecule 1 (ICAM1) in reinforcing GSC stemness and tumorigenicity, contributing to an immunosuppressive microenvironment through the β-catenin/PD-L1 signaling pathway. We demonstrate that modulating ICAM1 levels directly influences GSC self-renewal, proliferation, and tumorigenic capacity. Mechanistically, ICAM1 interacts with ZNRF3, a transmembrane E3 ligase, promoting ZNRF3 autoubiquitination and membrane clearance, which subsequently stabilizes LRP6. This interaction highlights PD-L1 as a critical ‘don’t eat me’ signal in ICAM1-mediated stemness and immune evasion, regulated transcriptionally by β-catenin and targetable by ICG001, a specific inhibitor of TCF/β-catenin-mediated transcription. Notably, combined treatment with anti-ICAM1 and anti-PD-1 resulted in the most effective tumor inhibition and significantly prolonged survival in ICAM1-overexpressing GBM models. Furthermore, CyTOF analysis revealed that ICAM1 overexpression reduces cytotoxic CD8+ T cell populations through PD-L1/PD-1 interactions, a process reversible by PD-1 blockade. Collectively, our findings underscore the therapeutic potential of co-targeting ICAM1 and PD-1 in GBM, offering a novel strategy to counteract GSC-driven immune evasion.