{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:38Z","timestamp":1787028578839,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["NRF-2017R1A2B3002227"],"award-info":[{"award-number":["NRF-2017R1A2B3002227"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["NRF-2020R1A5A2017323"],"award-info":[{"award-number":["NRF-2020R1A5A2017323"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tumor angiogenesis is a critical driver of cancer progression; however, current anti-angiogenic therapies remain limited by resistance and toxicity. Hypoxia within the tumor microenvironment induces hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1), which promotes aberrant angiogenesis by upregulating vascular endothelial growth factor (VEGF) and, subsequently, delta-like ligand 4 (DLL4) in endothelial cells. A systematic screening of flavanone derivatives was performed to identify compounds capable of dual inhibition of HIF-1\u03b1 and DLL4. Among 16 natural compounds evaluated, isoxanthohumol (IXN), a prenylated flavanone, emerged as the most potent, suppressing both hypoxia-induced HIF-1\u03b1 accumulation in tumor cells and VEGF-induced DLL4 expression in endothelial cells. IXN markedly inhibited endothelial proliferation, migration, and tube formation in vitro. In a Lewis lung carcinoma (LLC) mouse syngeneic model, IXN monotherapy reduced tumor growth and vessel density. Notably, combination treatment with IXN and anti-PD-1 immunotherapy produced greater anti-tumor effects than either monotherapy. This combination enhanced cytotoxic T cell infiltration into the tumor core, increased granzyme B expression, and induced widespread tumor cell apoptosis, consistent with improved vascular normalization. These findings identify IXN as a promising dual-targeting agent that inhibits both HIF-1\u03b1 and DLL4 and demonstrate its potential to enhance immune checkpoint blockade. Simultaneous targeting of hypoxia-driven and VEGF-DLL4-mediated angiogenic pathways represents a compelling therapeutic strategy to overcome the limitations of current anti-angiogenic and immunotherapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms27031576","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T15:24:19Z","timestamp":1770305059000},"page":"1576","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual Targeting of HIF-1\u03b1 and DLL4 by Isoxanthohumol Potentiates Immune Checkpoint Blockade"],"prefix":"10.3390","volume":"27","author":[{"given":"Doyoung","family":"Kim","sequence":"first","affiliation":[{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7999-4119","authenticated-orcid":false,"given":"Jihye","family":"You","sequence":"additional","affiliation":[{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1486-2925","authenticated-orcid":false,"given":"So Hee","family":"Bae","sequence":"additional","affiliation":[{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Hak","family":"Jeong","sequence":"additional","affiliation":[{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9885-3447","authenticated-orcid":false,"given":"Jong Hwa","family":"Jung","sequence":"additional","affiliation":[{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7337-1812","authenticated-orcid":false,"given":"Jeong Ah","family":"Kim","sequence":"additional","affiliation":[{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5756-7169","authenticated-orcid":false,"given":"You Mie","family":"Lee","sequence":"additional","affiliation":[{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/35025220","article-title":"Angiogenesis in cancer and other diseases","volume":"407","author":"Carmeliet","year":"2000","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s12272-022-01389-z","article-title":"Crosstalk between angiogenesis and immune regulation in the tumor microenvironment","volume":"45","author":"Kim","year":"2022","journal-title":"Arch. 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