# Targeting hypoxic exosomal IGFBP2 overcomes CD47-mediated immune evasion in glioblastoma

## TL;DR

This study identifies a new pathway in glioblastoma where hypoxia promotes immune evasion through exosomal IGFBP2 and CD47, and shows that blocking both can improve treatment outcomes.

## Contribution

The study reveals a novel hypoxia-driven mechanism involving exosomal IGFBP2 and CD47 in glioblastoma immune evasion.

## Key findings

- Hypoxia increases IGFBP2 expression and exosome secretion in glioblastoma.
- Exosomal IGFBP2 enhances CD47 expression and inhibits macrophage phagocytosis.
- Blocking both IGFBP2 and CD47 synergistically suppresses tumor growth in models.

## Abstract

Glioblastoma (GBM) acquires malignant traits through complex molecular adaptations that sustain immune evasion, often characterized by hypoxia and overexpression of the phagocytosis checkpoint CD47. However, the role of hypoxic drivers coordinating CD47-dependent immune evasion remains poorly defined. Here, we integrated single cell RNA sequencing and proteomic analysis to identify that insulin-like growth factor binding protein 2 (IGFBP2) was co-expressed with CD47 in hypoxic mesenchymal-like GBM subpopulations, synergistically promoting tumor progression and immune evasion. Mechanically, hypoxia induced IGFBP2 expression via HIF-2α-mediated transcriptional activation and further increased IGFBP2-positive exosome secretion through HIF-1α-dependent RAB3A upregulation. Moreover, IGFBP2 was predominantly localized on the exosome surface via integrin α5β1 and activated integrin/FAK/STAT3 signaling to enhance CD47 expression and inhibit macrophage phagocytosis. Clinically, serum exosomal IGFBP2 levels correlated with tumor grade and could serve as a diagnostic biomarker. Importantly, combinatorial blockade of IGFBP2 and CD47 synergistically suppressed tumor growth and prolonged survival in orthotopic GBM models. Together, our findings uncovered the hypoxia-exosomal IGFBP2-CD47 axis in GBM immune evasion and provided a compelling rationale for combination therapy to improve immunotherapy efficacy in GBM.