Novel CHI3L1-Associated Angiogenic Phenotypes Define Glioma Microenvironments: Insights From Multi-Omics Integration

Abstract

The CHI3L1 signaling pathway significantly influences glioma angiogenesis, but its role in the tumor microenvironment (TME) remains elusive. We propose a novel CHI3L1-associated vascular phenotype classification for glioma through integrative analyses of multiple datasets with bulk and single-cell transcriptome, genomics, digital pathology, and clinical data. We investigated the biological characteristics, genomic alterations, therapeutic vulnerabilities, and immune profiles within these phenotypes through a comprehensive multi-omics approach. We constructed the vascular-related risk (VR) score based on CHI3L1-associated vascular signatures (CAVS) identified by machine learning algorithms. Utilizing unsupervised consensus clustering, gliomas were stratified into three distinct vascular phenotypes: Cluster A, marked by high vascularization and stromal activation with a relatively low levels of tumor-infiltrating lymphocytes (TILs); Cluster B, characterized by moderate vascularization and stromal activity, coupled with a high density of TILs; and Cluster C, defined by low vascularization and sparse immune cell infiltration. We observed that the CAVS effectively indicated glioma-associated angiogenesis and immune suppression by single-cell RNA-seq analysis. Moreover, the high-VR-score group exhibited enhanced angiogenic activity, reduced immune response, resistance to immunotherapy, and poorer clinical outcomes. The VR score independently predicted glioma prognosis and, combined with a nomogram, provided a robust clinical decision-making tool. Potential drug prediction based on transcription factors for high-risk patients was also performed. Our study reveals that CHI3L1-associated vascular phenotypes shape distinct immune landscapes in gliomas, offering insights for optimizing therapeutic strategies to improve patient outcomes.