{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:52:05Z","timestamp":1791305525263,"version":"4.3.1"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Defense\/War Congressionally Directed Medical Research Program","award":["KC220016"],"award-info":[{"award-number":["KC220016"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Yale School of Medicine","award":["Louis Goodman and Alfred Gilman Yale Scholar Fund"],"award-info":[{"award-number":["Louis Goodman and Alfred Gilman Yale Scholar Fund"]}]},{"name":"NIH\/NCI","award":["1R37CA279822-01"],"award-info":[{"award-number":["1R37CA279822-01"]}]},{"name":"DF\/HCC Kidney Cancer SPORE","award":["P50CA101942"],"award-info":[{"award-number":["P50CA101942"]}]},{"name":"Yale Cancer Center","award":["P30CA016359"],"award-info":[{"award-number":["P30CA016359"]}],"id":[{"id":"https:\/\/ror.org\/03j7sze86","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Hypoxia-inducible factor 2\u03b1 (HIF-2\u03b1) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC) and a therapeutic target of the small-molecule inhibitor belzutifan. Genetic studies in murine models have suggested that hypoxia signaling may support T cell effector programs, raising concern that HIF-2\u03b1 inhibition could impair antitumor immunity. However, whether pharmacologic HIF-2\u03b1 inhibition alters human T cell biology remains unknown. Here, we investigated the cell-intrinsic effects of\n                    <jats:italic>EPAS1<\/jats:italic>\n                    (encoding HIF-2\u03b1) perturbation in primary human T cells. CRISPR\/Cas9-mediated deletion of HIF-2\u03b1 demonstrated no notable transcriptional effects. Similarly, pharmacologic treatment with belzutifan produced minimal transcriptional changes and did not impair proliferation, cytokine production, polyfunctionality, or cytotoxic activity in T cells derived from healthy donor peripheral blood, peripheral blood from patients with ccRCC, or tumor-infiltrating lymphocytes under hypoxic conditions. High- dimensional immunophenotyping revealed preserved T cell differentiation and activation states following pharmacologic HIF-2\u03b1 inhibition\n                    <jats:italic>in vitro<\/jats:italic>\n                    and in peripheral blood from patients receiving HIF-2\u03b1 inhibitor therapy. Together, these findings demonstrate that pharmacologic HIF-2\u03b1 inhibition preserves key effector programs, providing a mechanistic basis for the immunologic safety of HIF-2\u03b1\u2013targeted therapy in ccRCC.\n                  <\/jats:p>","DOI":"10.1172\/jci204613","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:00:53Z","timestamp":1791302453000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacologic HIF-2\u03b1 inhibition preserves T cell effector function in clear cell renal cell carcinoma"],"prefix":"10.1172","author":[{"given":"Katrine N.","family":"Madsen","sequence":"first","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soki","family":"Kashima","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Soulati","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Wirth","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhiro","family":"Ito","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary A.","family":"Yochum","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"Moritz","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Walker","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Machaalani","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fady","family":"Ghali","sequence":"additional","affiliation":[{"name":"Department of Urology, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Kenney","sequence":"additional","affiliation":[{"name":"Department of Urology, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adebowale","family":"Adeniran","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hurwitz","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9201-3217","authenticated-orcid":true,"given":"Toni K.","family":"Choueiri","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Braun","sequence":"additional","affiliation":[{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,6]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/204613\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:00:54Z","timestamp":1791302454000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/204613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":0,"alternative-id":["10.1172\/JCI204613"],"URL":"https:\/\/doi.org\/10.1172\/jci204613","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]}}}