{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:44Z","timestamp":1787027804622,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01CA269025"],"award-info":[{"award-number":["R01CA269025"]}]},{"name":"NIH","award":["T32AI007413"],"award-info":[{"award-number":["T32AI007413"]}]},{"name":"NIH","award":["F31CA281079"],"award-info":[{"award-number":["F31CA281079"]}]},{"name":"NIH","award":["R01CA268426"],"award-info":[{"award-number":["R01CA268426"]}]},{"name":"NIH","award":["R01CA260752"],"award-info":[{"award-number":["R01CA260752"]}]},{"name":"NIH","award":["R01CA271510"],"award-info":[{"award-number":["R01CA271510"]}]},{"award":["R01CA269025"],"award-info":[{"award-number":["R01CA269025"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32AI007413"],"award-info":[{"award-number":["T32AI007413"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"award":["F31CA281079"],"award-info":[{"award-number":["F31CA281079"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA268426"],"award-info":[{"award-number":["R01CA268426"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA260752"],"award-info":[{"award-number":["R01CA260752"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA271510"],"award-info":[{"award-number":["R01CA271510"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Michigan Rogel Cancer Center"},{"id":[{"id":"https:\/\/ror.org\/05asdy483","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal microenvironment and profound hypoxia, which contribute to therapeutic resistance. Using an in vitro system incorporating pancreatic cancer cells and cancer-associated fibroblasts (CAFs), we show that hypoxia suppresses CD8+ T cell accumulation and, in combination with cancer cell- and CAF-derived factors, further impairs T cell fitness by increasing cell death and reducing proliferation. Although the combination of hypoxia and cancer cell\/CAF-derived factors enhances IFN\u03b3 and granzyme B expression in CD8+ T cells on a per-cell basis, the overall number of functional effector T cells is markedly reduced. Analysis of human PDAC single-cell RNA sequencing data corroborates these findings, revealing that CD8+ T cells enriched for hypoxia signatures exhibit elevated apoptosis and stress-response pathways. Furthermore, hypoxia is associated with downregulation of stemness-related genes and upregulation of terminal differentiation markers. Together, these data suggest that the integration of intrinsic hypoxic responses and extrinsic cues from tumor cells and CAFs impairs CD8+ T cell fitness and correlates with a terminally differentiated, dysfunctional T cell state.<\/jats:p>","DOI":"10.3390\/cancers18101508","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T20:14:16Z","timestamp":1778530456000},"page":"1508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoxia Impairs CD8+ T Cell Fitness and Is Associated with a Dysfunctional CD8+ T Cell State in Pancreatic Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-181X","authenticated-orcid":false,"given":"Ashley M.","family":"Mello","sequence":"first","affiliation":[{"name":"Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Pasca di Magliano","sequence":"additional","affiliation":[{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3955-7389","authenticated-orcid":false,"given":"Kyoung Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","first-page":"36","article-title":"Genetics and biology of pancreatic ductal adenocarcinoma","volume":"39","author":"Ying","year":"2025","journal-title":"Genes. 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