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Here, we report a \u201ccap-linker\u201d strategy to modify the vesicular stomatitis virus (VSV) glycoprotein (G protein, VSV-G\n                    <jats:sup>IN<\/jats:sup>\n                    ). The modified VSV (Pro-VSV\n                    <jats:sup>IN<\/jats:sup>\n                    ) 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-VSV\n                    <jats:sup>IN<\/jats:sup>\n                    is armed with a single-chain IL-12 (Pro-VSV\n                    <jats:sup>IN<\/jats:sup>\n                    -IL-12) and systemically injected into MC38 tumor-bearing mice, Pro-VSV\n                    <jats:sup>IN<\/jats:sup>\n                    -IL-12 eradicates established tumors while avoiding systemic toxicity, and elicits long-term anti-tumor immune memory. Systemic administration of Pro-VSV\n                    <jats:sup>IN<\/jats:sup>\n                    -IL-12 also markedly inhibits the growth of metastatic cancers in the lung. The efficacy of Pro-VSV\n                    <jats:sup>IN<\/jats:sup>\n                    -IL-12 was further improved when combined with PD-1 checkpoint blockade. Compared to WT VSV\n                    <jats:sup>IN<\/jats:sup>\n                    that carries IL-12, intravenously injected Pro-VSV\n                    <jats:sup>IN<\/jats:sup>\n                    -IL-12 leads to strong Th1 immunity, near abolishment of regulatory T cells, and potent CD8\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41392-026-02888-x","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:02:25Z","timestamp":1792450945000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Matrix metalloproteinase-guided targeting of vesicular stomatitis virus to tumors following systemic administration"],"prefix":"10.1038","volume":"11","author":[{"given":"Eileen Victoria","family":"Theune","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Theune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham","family":"Ahmadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conner C.","family":"Chiari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9137-1103","authenticated-orcid":false,"given":"Neha","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory","family":"Geyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Tonne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel","family":"Metko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olamide T.","family":"Olaoba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella China","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5843-8273","authenticated-orcid":false,"given":"Jianbin","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangfu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7332-1871","authenticated-orcid":false,"given":"Penghua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan R.","family":"Jellison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Vella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Vile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kepeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"2888_CR1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00640-25","volume":"99","author":"JZ Xu","year":"2025","unstructured":"Xu, J. 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