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Oncolytic viruses represent a promising treatment strategy, as they selectively replicate within cancer cells and lyse them, potentially including those in hypoxic tumor regions. Here, we examined how hypoxic conditions influence the activity of enadenotucirev (EnAd), a clinically relevant group B oncolytic adenovirus previously detected in hypoxic areas of xenograft tumors. We demonstrated that hypoxia enhances virus production by boosting transcription and translation of immediate-early, early, and late adenoviral genes. The immediate-early gene\n                    <jats:italic>E1A<\/jats:italic>\n                    was upregulated within 2\u2009h (17-fold) after virus entry under hypoxia, driven by a conserved hypoxia-response element (HRE) in its promoter. Mechanistic studies revealed that the hypoxia-inducible factor (HIF)-2\u03b1 and HIF-1\u03b2 heterodimers bind to this HRE, transactivating\n                    <jats:italic>E1A<\/jats:italic>\n                    . By inducing E1A expression, hypoxia also elevated viral genome synthesis, structural protein production, and therapeutic transgene expression, underscoring the potential of EnAd to target the hypoxic tumor microenvironment. This is the first report of a functional HRE in a human adenovirus, conserved across 59 adenovirus genotypes, and identifies hypoxia as a driver of enhanced oncolytic activity with implications for adenovirus-based therapies in solid tumors.\n                  <\/jats:p>","DOI":"10.1038\/s41392-026-02895-y","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:02:07Z","timestamp":1786406527000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia increases the activity of oncolytic adenoviruses through HIF-2\u03b1-stimulated E1A expression"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4436-360X","authenticated-orcid":false,"given":"Egon J.","family":"Jacobus","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique N.","family":"Lafleur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry D.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Mole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3825-0841","authenticated-orcid":false,"given":"Leonard W.","family":"Seymour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2895_CR1","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/s41392-023-01332-8","volume":"8","author":"Z Chen","year":"2023","unstructured":"Chen, Z., Han, F., Du, Y., Shi, H. & Zhou, W. 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