{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T03:07:44Z","timestamp":1782961664726,"version":"3.54.5"},"reference-count":69,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"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":"publisher","award":["NRF-2016M3A9B6948342, NRF-2018M3A9D3079288, NRF-2020R1A2C2103061, NRF-2013M3A9D3046248, NRF-2018R1A4A1025985, NRF-2018R1D1A1B07041442"],"award-info":[{"award-number":["NRF-2016M3A9B6948342, NRF-2018M3A9D3079288, NRF-2020R1A2C2103061, NRF-2013M3A9D3046248, NRF-2018R1A4A1025985, NRF-2018R1D1A1B07041442"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002642","name":"Korea University","doi-asserted-by":"publisher","award":["Korea University Grant"],"award-info":[{"award-number":["Korea University Grant"]}],"id":[{"id":"10.13039\/501100002642","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>NK cells are the predominant innate lymphocyte subsets specialized to kill malignant tumor cells. In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and immunosuppressive phenotypes, hence a strategy to restore NK function is critical for successful tumor immunotherapy. Here, we present evidence that pre-activation and subsequent HIF-1\u03b1-dependent metabolic shift of NK cells from oxidative phosphorylation into glycolysis are keys to overcome hypoxia-mediated impairment in NK cell survival, proliferation, and tumor cytotoxicity. Specifically, exposing NK cells to 7\u20139 days of normoxic culture followed by a pO2 of 1.5% hypoxia led to a highly potent effector phenotype via HIF-1\u03b1 stabilization and upregulation of its target genes, BNIP3, PDK1, VEGF, PKM2, and LDHA. RNA sequencing and network analyses revealed that concomitant reduction of p21\/p53 apoptotic pathways along with upregulation of cell cycle-promoting genes, CCNE1, CDC6, CDC20, and downregulation of cell cycle-arrest genes, CDKN1A, GADD45A, and MDM2 were accountable for superior expansion of NK cells via ERK\/STAT3 activation. Furthermore, HIF-1\u03b1-dependent upregulation of the NKp44 receptor in hypoxia-exposed NK cells resulted in increased killing against K562, CEM, and A375 tumor targets both in-vitro and in-vivo tumor clearance assays. Therefore, hypoxic exposure on pre-activated proliferating NK cells triggered HIF-1\u03b1-dependent pathways to initiate coordinated regulation of cell cycle, apoptosis, and cytotoxicity at the global gene transcription level. Our results uncover a previously unidentified role of HIF-1\u03b1-mediated metabolic reprogramming that can reverse impaired NK effector phenotypes to generate requisite numbers of functionally robust NK cells for adoptive cellular therapy for clinical evaluation.<\/jats:p>","DOI":"10.3390\/cancers13081904","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T12:11:00Z","timestamp":1618488660000},"page":"1904","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Hypoxia-Driven HIF-1\u03b1 Activation Reprograms Pre-Activated NK Cells towards Highly Potent Effector Phenotypes via ERK\/STAT3 Pathways"],"prefix":"10.3390","volume":"13","author":[{"given":"Seon Ah","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunwon","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Life Science, University of Seoul, Seoul 02504, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-5760","authenticated-orcid":false,"given":"Min Hwa","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehyun","family":"Chae","sequence":"additional","affiliation":[{"name":"Korea Brain Bank, Korea Brain Research Institute, Daegu 41068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassian","family":"Yee","sequence":"additional","affiliation":[{"name":"Departments of Melanoma Medical Oncology and Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daehee","family":"Hwang","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunsung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Life Science, University of Seoul, Seoul 02504, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5378-9258","authenticated-orcid":false,"given":"Kyung-Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea"},{"name":"Department of Biomedical Engineering, Center for Bio-Integrated Electronics, Simpson Querrey Institute, Northwestern University, Evanston, IL 60208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/ni.3518","article-title":"Targeting natural killer cells in cancer immunotherapy","volume":"17","author":"Guillerey","year":"2016","journal-title":"Nat. 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