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We utilized computer-aided drug discovery and cell-based reporter assays to identify dual HIF-1\/2 inhibitors, which bind directly to highly conserved domains of HIF-1\u03b1 and HIF-2\u03b1, disrupt dimerization with HIF-1\u03b2, and trigger proteasomal degradation, thereby inhibiting HIF-1\/2 transcriptional activity. These inhibitors and derivative compounds block growth and vascularization of breast, colorectal, head\/neck, melanoma, and prostate tumors as monotherapy, and overcome resistance to anti-CTLA-4 or anti-PD-1 immunotherapy, with an aggregate complete response rate of over 50%, through reprogramming of the tumor immune cell microenvironment. Compared with the HIF-2\u2013selective inhibitors belzutifan and PT2385, dual HIF-1\/2 inhibitor 1.21S9N showed superior activity against breast and colorectal cancer models, respectively. PT2385 caused breathing abnormalities, whereas 1.21S9N did not. The drugs are orally bioavailable, and no safety concerns were identified even after extended or supratherapeutic dosing.<\/jats:p>","DOI":"10.1084\/jem.20251009","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:20:52Z","timestamp":1769757652000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting conserved domains of hypoxia-inducible factors for cancer therapy"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2002-3117","authenticated-orcid":true,"given":"Shaima","family":"Salman","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/037zgn354","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Cell Engineering, and Armstrong Oxygen Biology Research Center, Johns Hopkins University School of Medicine 1 Department of Genetic Medicine, , Baltimore, 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