{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:16:32Z","timestamp":1789661792490,"version":"4.0.1"},"reference-count":186,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chronic graft-versus-host disease (cGVHD), a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), arises from donor immune cell-mediated tissue damage, chronic inflammation, and fibrosis. Current therapies fail to adequately address fibrotic progression and heighten infection risks, underscoring the need for targeted strategies. Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1), a pivotal regulator, emerges as a potential therapeutic target by orchestrating immunometabolic homeostasis, suppressing fibrosis, preserving gut microbiota balance, and retaining graft-versus-leukemia (GVL) effects. However, clinical translation necessitates overcoming challenges in tissue specificity and off-target effects. Smart nanodelivery systems hold promise for enhancing precision to enable localized HIF-1\u03b1 pathway modulation. This review highlights the multidimensional roles of HIF-1\u03b1 in cGVHD pathogenesis and proposes nanotherapeutic approaches to reconcile immunofibrotic imbalances, advancing a paradigm shift in cGVHD management while preserving GVL efficacy.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1605669","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T04:10:18Z","timestamp":1753675818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting hypoxia-inducible factor 1\u03b1 in chronic graft-versus-host disease to enhance graft-versus-leukemia responses: implications for nanotherapeutics"],"prefix":"10.3389","volume":"16","author":[{"given":"Yimin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2016.09.023","article-title":"The biology of chronic graft-versus-host disease: A task force report from the national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease","volume":"23","author":"Cooke","year":"2017","journal-title":"Biol Blood Marrow Transplant"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2242","article-title":"Graft-versus-host disease is enhanced by extracellular atp activating P2x7r","volume":"16","author":"Wilhelm","year":"2010","journal-title":"Nat Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3517","article-title":"Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage","volume":"20","author":"Schwab","year":"2014","journal-title":"Nat Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s0041-1345(96)00441-1","article-title":"Specificity of effector mechanisms in syngeneic graft-vs-host disease: recognition of the mhc class ii invariant chain peptide (Clip)","volume":"29","author":"Hess","year":"1997","journal-title":"Transplant Proc"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92111","article-title":"An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition","volume":"2","author":"Forcade","year":"2017","journal-title":"JCI Insight"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-09-668145","article-title":"Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice","volume":"127","author":"Jin","year":"2016","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-07-686642","article-title":"Classification systems for chronic graft-versus-host disease","volume":"129","author":"Lee","year":"2017","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1182\/blood-2016-06-686618","article-title":"Chronic graft-versus-host disease: biological insights from preclinical and clinical studies","volume":"129","author":"MacDonald","year":"2017","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-10-464198","article-title":"Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease","volume":"121","author":"Inamoto","year":"2013","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022735","article-title":"Chronic graft-versus-host disease: unresolved complication or ancient history","volume":"144","author":"Pidala","year":"2024","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.jaad.2022.12.023","article-title":"Chronic graft-versus-host disease. 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