{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:24:28Z","timestamp":1786947868318,"version":"build-2736575974"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"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>\n                    Invariant natural killer T (iNKT) cells are promising candidates for allogeneic cellular immunotherapy, but the metabolic pathways that support their effector function in nutrient-limited tumor microenvironments remain poorly defined. Human iNKT cells segregate into CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD4\u207bCD8\u207b double-negative (DN) subsets with distinct functional profiles, yet whether they use divergent metabolic strategies to sustain IFN-\u03b3 production is unknown. Here we show that\n                    <jats:italic>in vitro<\/jats:italic>\n                    -expanded human CD4\n                    <jats:sup>+<\/jats:sup>\n                    and DN iNKT cells employ distinct metabolic programs that differentially support IFN-\u03b3 secretion under nutrient stress. DN iNKT cells exhibit higher Glut1 expression and a more glycolytic phenotype, with IFN-\u03b3 production that is sensitive to extracellular glucose withdrawal and glycolytic inhibition. In contrast, CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells display high spare respiratory capacity, preferentially engage glutamine-supported mitochondrial respiration, and maintain IFN-\u03b3 production despite glucose deprivation or 2-DG inhibitor treatment. CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells generated excess ATP through oxidative metabolism, accumulated intracellular glycogen stores during expansion\n                    <jats:italic>in vitro<\/jats:italic>\n                    , and subsequently mobilized this glycogen to support IFN-\u03b3 production in tumor-exhausted media. Using a xenograft model of EBV-driven B cell lymphoma, we show that adoptively transferred human CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells infiltrate tumors\n                    <jats:italic>in vivo<\/jats:italic>\n                    and are associated with elevated intratumoral IFN-\u03b3. These findings identify a distinctive combination of high mitochondrial oxidative capacity, glutamine utilization, and glycogen storage that endows human CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT cells with exceptional metabolic resilience, suggesting that CD4\n                    <jats:sup>+<\/jats:sup>\n                    iNKT-based products may provide a particularly valuable platform for adoptive cellular immunotherapy.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1894113","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:26:15Z","timestamp":1786944375000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Human CD4+ iNKT cells have highly oxidative metabolism and use glycogen reserves to sustain IFN-\u03b3 production in nutrient-limited environments"],"prefix":"10.3389","volume":"17","author":[{"given":"Niharika M.","family":"Patankar","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidus","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhila S.","family":"Bharadwaj","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny E.","family":"Gumperz","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00384","article-title":"Novel approaches to exploiting invariant NKT cells in cancer immunotherapy","volume":"9","author":"Wolf","year":"2018","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13205174","article-title":"The current landscape of NKT cell immunotherapy and the hills 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