COL6A2: A Key Survival-Related Gene and Restricting Antitumor Immunity in Glioblastoma

Abstract

Glioblastoma (GBM) is an aggressive malignant brain tumor, characterized by a poor prognosis and a limited response to chemoradiotherapy and immunotherapy. Increasing evidence indicates that the extracellular matrix (ECM), particularly collagen proteins, contributes to tumor progression and immune evasion. In this study, we identified COL1A2, COL6A2, COL8A1, and COL8A2 as survival-related genes that were overexpressed in GBM and significantly upregulated in short-term survivors. Subsequently, COL6A2 was verified to be associated with chemotherapy and immunosuppression. Functional assays demonstrated that COL6A2 promotes GBM cell proliferation, invasion, and chemoresistance. Cytometry by time-of-flight (CyTOF) and Tumor Immune Estimation Resource (TIMER) analysis revealed that high COL6A2 expression correlates with immunosuppressive features in the tumor microenvironment, particularly the accumulation of immature dendritic cells (DCs) and impaired cytotoxic T-cell activity. Mechanistically, COL6A2 silencing restored DCs' activation and enhanced the infiltration and function of effector immune cells. Our findings highlight COL6A2 as a key oncogenic and immunomodulatory ECM component in GBM and suggest that targeting collagen-mediated immune suppression may improve therapeutic outcomes in GBM patients.