Background: Oncolytic virotherapy holds promise for Glioblastoma (GBM), but the intratumoral replication kinetics of oncolytic viruses and resistance mechanisms of tumor cells remain poorly understood, limiting the development of precise combination strategies to improve durable efficacy.
Methods: Using the translational Resistance Exploration via Synchronized Clinical-Unit Experiments (RESCUE) framework that synchronizes clinical trials with patient-derived xenograft (PDX) models, we profiled the replication kinetics of the oncolytic adenovirus YSCH-01 and performed genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation screening to identify key genes restricting sustained viral replication. Through spatial transcriptomics combined with histological analyses, we delineated the spatial determinants that limit viral dissemination following oncolytic virus administration.
Results: We identified B‑cell lymphoma/leukemia 10 (BCL10) as a key suppressor of sustained viral replication. Viral infection activated the BCL10-NF-κB pathway, triggering paracrine secretion of interleukin-8 (IL-8) from infected tumor cells. Interleukin-8 induced senescence and fibrotic remodeling in neighboring uninfected cells, forming a previously unrecognized Tumor Self-Rampart (TSR)-a concentric barrier of senescent and fibrotic tumor cells that spatially confines viral propagation. Tumor Self-Rampart was validated in both PDX and patient tumors. Interleukin-8 blockade with Reparixin or peri-dosing glucocorticoids effectively disrupted TSR formation, prolonged viral persistence, and enhanced therapeutic efficacy.
Conclusion: Glioblastoma mounts a spatial self-protective defense through IL-8-driven TSR formation that restricts oncolytic virus spread. Interleukin-8 functions as both a pharmacodynamic biomarker and a therapeutic target, and its inhibition provides a rational strategy to overcome resistance and optimize GBM virotherapy.
Keywords: CRISPR screening; glioblastoma; interleukin-8; oncolytic adenovirus; tumor self-rampart.
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