Matrix metalloproteinase-guided targeting of vesicular stomatitis virus to tumors following systemic administration.
8 affiliations
- 1Department of Immunology, University of Connecticut School of Medicine, UConn Health, Farmington, CT, USA.
- 2Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
- 3Department of Surgery, University of Connecticut School of Medicine, UConn Health, Farmington, CT, USA.
- 4Johns Hopkins University, Baltimore, MD, USA.
- 5University of Connecticut, Storrs, CT, USA.
- 6Department of Immunology, Mayo Clinic, Rochester, MN, USA.
- 7Comprehensive Cancer Centre, School of Cancer & Pharmaceutical Sciences, School of Immunology and Microbial Sciences, King's College London, London, UK.
- 8Department of Immunology, University of Connecticut School of Medicine, UConn Health, Farmington, CT, USA. [email protected].
Abstract
The lack of tumor-specific targeting by oncolytic viruses (OVs) restricts their therapeutic potential. Here, we report a "cap-linker" strategy to modify the vesicular stomatitis virus (VSV) glycoprotein (G protein, VSV-GIN). The modified VSV (Pro-VSVIN) loses its ability to infect cells until present in the tumor microenvironment, where the linker is cleaved by tumor-enriched matrix metalloproteinases (MMPs). When Pro-VSVIN is armed with a single-chain IL-12 (Pro-VSVIN-IL-12) and systemically injected into MC38 tumor-bearing mice, Pro-VSVIN-IL-12 eradicates established tumors while avoiding systemic toxicity, and elicits long-term anti-tumor immune memory. Systemic administration of Pro-VSVIN-IL-12 also markedly inhibits the growth of metastatic cancers in the lung. The efficacy of Pro-VSVIN-IL-12 was further improved when combined with PD-1 checkpoint blockade. Compared to WT VSVIN that carries IL-12, intravenously injected Pro-VSVIN-IL-12 leads to strong Th1 immunity, near abolishment of regulatory T cells, and potent CD8⁺ T cell activation and clonal expansion in tumors. This preclinical work demonstrates a new tumor-specific targeting strategy of VSV for enhanced immunotherapy safety with superior efficacy.
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BibTeX
@article{theune2026matrix,
title = {{Matrix metalloproteinase-guided targeting of vesicular stomatitis virus to tumors following systemic administration.}},
author = {Eileen Victoria Theune and William C Theune and Elham Ahmadi and Conner C Chiari and Neha Singh and Rory Geyer and Jason Tonne and Muriel Metko and Olamide T Olaoba and Isabella China Wang and Dylan Dai and Jianbin Ruan and Robert Clark and Guangfu Li and Penghua Wang and Evan R Jellison and Anthony T Vella and Richard Vile and Kepeng Wang},
journal = {Signal transduction and targeted therapy},
year = {2026},
month = oct,
doi = {10.1038/s41392-026-02888-x},
url = {https://europepmc.org/article/MED/42897128},
note = {CC BY},
}
RIS
TY - JOUR
TI - Matrix metalloproteinase-guided targeting of vesicular stomatitis virus to tumors following systemic administration.
AU - Eileen Victoria Theune
AU - William C Theune
AU - Elham Ahmadi
AU - Conner C Chiari
AU - Neha Singh
AU - Rory Geyer
AU - Jason Tonne
AU - Muriel Metko
AU - Olamide T Olaoba
AU - Isabella China Wang
AU - Dylan Dai
AU - Jianbin Ruan
AU - Robert Clark
AU - Guangfu Li
AU - Penghua Wang
AU - Evan R Jellison
AU - Anthony T Vella
AU - Richard Vile
AU - Kepeng Wang
PY - 2026
DA - 2026/10/20
JO - Signal transduction and targeted therapy
DO - 10.1038/s41392-026-02888-x
UR - https://europepmc.org/article/MED/42897128
AB - The lack of tumor-specific targeting by oncolytic viruses (OVs) restricts their therapeutic potential. Here, we report a "cap-linker" strategy to modify the vesicular stomatitis virus (VSV) glycoprotein (G protein, VSV-GIN). The modified VSV (Pro-VSVIN) loses its ability to infect cells until present in the tumor microenvironment, where the linker is cleaved by tumor-enriched matrix metalloproteinases (MMPs). When Pro-VSVIN is armed with a single-chain IL-12 (Pro-VSVIN-IL-12) and systemically injected into MC38 tumor-bearing mice, Pro-VSVIN-IL-12 eradicates established tumors while avoiding systemic toxicity, and elicits long-term anti-tumor immune memory. Systemic administration of Pro-VSVIN-IL-12 also markedly inhibits the growth of metastatic cancers in the lung. The efficacy of Pro-VSVIN-IL-12 was further improved when combined with PD-1 checkpoint blockade. Compared to WT VSVIN that carries IL-12, intravenously injected Pro-VSVIN-IL-12 leads to strong Th1 immunity, near abolishment of regulatory T cells, and potent CD8⁺ T cell activation and clonal expansion in tumors. This preclinical work demonstrates a new tumor-specific targeting strategy of VSV for enhanced immunotherapy safety with superior efficacy.
SN - 2095-9907
SN - 2059-3635
ER -