Zika virus oncolytic signaling reverts immunosuppressive and angiogenic glioblastoma microenvironment in vitro and in vivo

Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor, remains refractory to conventional therapies, characterized by high relapse rates and an extremely poor clinical prognosis. Oncolytic viruses represent a promising therapeutic frontier; specifically, Zika virus (ZIKV) has shown potent oncolytic activity against GBM in vitro and in vivo. However, its impact on the tumor microenvironment (TME) remains poorly understood. Here, we demonstrate that ZIKV modulates pivotal TME components, exerting a paracrine anti-angiogenic effect that impairs endothelial stabilization and reprogramming microglia toward an anti-tumoral phenotype. These findings were corroborated in vivo in GBM-bearing mice. Using unbiased RNA-Seq, we identified type III interferon (IFN) signaling as the primary mediator of this ZIKV-induced TME remodeling. Crucially, analysis of human glioma datasets reveals that the type III IFN receptor complex is highly expressed in patients. This identifies a high-risk population that possesses the molecular machinery to respond to this signaling axis. Exogenous treatment with type III IFN in vitro and in vivo successfully mimicked ZIKV’s anti-tumoral effects, reducing angiogenesis and promoting immune activation. Our results demonstrate that ZIKV acts as a powerful immunotherapeutic agent capable of shifting the TME toward an anti-tumoral state. By targeting a signaling axis characterized by high receptor density in treatment-refractory cases, this study identifies the type III IFN pathway as a therapeutic vulnerability and a promising strategy for patients who have failed conventional therapies.