Zika virus oncolytic signaling reverts immunosuppressive and angiogenic glioblastoma microenvironment in vitro and in vivo
- 1Universidade Federal do Rio de Janeiro/ King's College London
Abstract
Glioblastoma (GBM), the most aggressive primary brain tumor, remains refractory to conventional therapies, characterized by high relapse rates and 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, triggering paracrine anti-angiogenic signaling 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 revealed that the type III IFN receptor complex is highly expressed in patients, identifying a high-risk population equipped with the molecular machinery to respond to this 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 an immunotherapeutic agent capable of shifting the TME toward an anti-tumoral state, highlighting the type III IFN pathway as an actionable vulnerability and a promising strategy for patients failing conventional therapies.
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BibTeX
@misc{freitas2026zika,
title = {{Zika virus oncolytic signaling reverts immunosuppressive and angiogenic glioblastoma microenvironment in vitro and in vivo}},
author = {G. Pinheiro Alves de Freitas and J. H. Quintanilla and J. M. Janeiro and O. Brechko and R. Weinstock and G. Cardoso Atella and M. Villanueva Andrade and J. C.C.G. Ferreira and J. M.de Vasconcelos and J. Vianez and M. Bellio and A. TANURI and L. G. Dubois and F. R. S. Lima and V. Moura-Neto and L. M. Higa and P. Pestana Garcez},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.752714},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.752714v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Zika virus oncolytic signaling reverts immunosuppressive and angiogenic glioblastoma microenvironment in vitro and in vivo
AU - G. Pinheiro Alves de Freitas
AU - J. H. Quintanilla
AU - J. M. Janeiro
AU - O. Brechko
AU - R. Weinstock
AU - G. Cardoso Atella
AU - M. Villanueva Andrade
AU - J. C.C.G. Ferreira
AU - J. M.de Vasconcelos
AU - J. Vianez
AU - M. Bellio
AU - A. TANURI
AU - L. G. Dubois
AU - F. R. S. Lima
AU - V. Moura-Neto
AU - L. M. Higa
AU - P. Pestana Garcez
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.752714
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.752714v1
AB - Glioblastoma (GBM), the most aggressive primary brain tumor, remains refractory to conventional therapies, characterized by high relapse rates and 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, triggering paracrine anti-angiogenic signaling 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 revealed that the type III IFN receptor complex is highly expressed in patients, identifying a high-risk population equipped with the molecular machinery to respond to this 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 an immunotherapeutic agent capable of shifting the TME toward an anti-tumoral state, highlighting the type III IFN pathway as an actionable vulnerability and a promising strategy for patients failing conventional therapies.
ER -