Abstract
BACKGROUND: Oncolytic viruses (OVs) achieve selective cytolysis via tumor-specific entry receptor. However, the prevalence of OVs receptors in malignant tumors has not been fully determined yet. Here, we systematically identify and characterize critical cellular entry receptors for clinically relevant OVs, particularly focusing on SCARB2 expression and its potential therapeutic implications for oncolytic Enterovirus A71 (EV-A71) therapy in glioma. METHODS: A systematic literature review was performed to summarize key entry receptors of major oncolytic viruses. Transcriptomic and proteomic data from TCGA, CPTAC, HPA, GEPIA2, CGGA and clinical databases were analyzed to profile receptor expression and clinical relevance across cancer types, especially glioma. Immunofluorescence and RNAi assays in glioblastoma (GBM) cell lines were conducted to assess SCARB2 localization, expression, and cellular functional roles. RESULTS: Pan-cancer analyses revealed widespread overexpression of key viral receptors. SCARB2 significantly was overexpressed in glioma compared to brain tissues. Elevated SCARB2 protein levels were particularly noted in high-grade gliomas. Further in vitro assays confirmed SCARB2 localization primarily at the cell membrane in glioblastoma cells. Additionally, SCARB2 expression correlated with molecular subtype, immune subtype, and tumor-infiltrating lymphocyte composition in gliomas. Functional studies demonstrated that SCARB2 knockdown and EV-A71 infection markedly reduced GBM cell proliferation and enhanced cell apoptosis rate, suggesting its critical role in facilitating viral entry and subsequent antitumor effects. CONCLUSIONS: SCARB2 serves as a critical cellular receptor for EV-A71-mediated oncolytic activity in glioma. Elevated SCARB2 expression in GBM highlights its potential as both a therapeutic target and predictive biomarker for selecting glioma patients responsive to oncolytic EV-A71 therapy.