Hypoxic Endothelial-Cell-Derived Exosomal lnc-DKK3 Reprograms Tumor-Associated Macrophages via USP47/PD-L1/RelA Axis to Promote Glioma Progression

Abstract

The hypoxic microenvironment in gliomas critically contributes to malignant progression. This study investigates the functional role and molecular mechanisms of long noncoding RNAs derived from hypoxic endothelial cell exosomes in reprogramming tumor-associated macrophages and driving glioma progression. We identified a novel long noncoding RNA, lnc-DKK3, enriched in exosomes secreted by hypoxic endothelial cells. Nuclear-localized lnc-DKK3 suppresses PD-L1 ubiquitination in macrophages by binding to USP47, promoting M2-like polarization and immunosuppression. Additionally, the lnc-DKK3/USP47 axis stabilizes RelA, augmenting its transcriptional activity and collectively accelerating glioma progression. Thus, hypoxic endothelial-cell-derived lnc-DKK3 drives M2 polarization via the USP47/PD-L1 pathway and promotes glioma progression via the USP47/RelA axis, highlighting its therapeutic potential. To translate these insights, we developed a macrophage-specific CRISPR interference–liquid nanoparticle platform targeting the lnc-DKK3 super-enhancer and demonstrated its synergistic sensitization to anti-PD-1 therapy in preclinical models.