{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T16:45:51Z","timestamp":1780332351727,"version":"3.54.1"},"reference-count":27,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["RO1CA226983"],"award-info":[{"award-number":["RO1CA226983"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Saint Baldrick's Foundation","award":["587296"],"award-info":[{"award-number":["587296"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD+ by the enzyme Lactobacillus brevis NADH Oxidase (LbNOX), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if LbNOX promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing LbNOX have enhanced oxygen as well as lactate consumption and increased pyruvate production. LbNOX renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell\u2019s expressing LbNOX showed no increased antitumor efficacy over control CAR T-cells. We hypothesize that T cells in hostile environments face dual metabolic stressors of excessive NADH and insufficient ATP production. Accordingly, futile T-cell NADH oxidation by LbNOX is insufficient to promote tumor clearance.<\/jats:p>","DOI":"10.3390\/cells10092334","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T10:59:12Z","timestamp":1630925952000},"page":"2334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["CAR T-Cells Depend on the Coupling of NADH Oxidation with ATP Production"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7112-1537","authenticated-orcid":false,"given":"Juan","family":"Garcia-Canaveras","sequence":"first","affiliation":[{"name":"Department of Chemistry, Princeton University, Princeton, NJ 08544, USA"},{"name":"Lewis-Singer Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Heo","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Trefely","sequence":"additional","affiliation":[{"name":"A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Leferovich","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"The Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Philipson","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Ghassemi","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Milone","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmund","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19140, USA"},{"name":"Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel","family":"Snyder","sequence":"additional","affiliation":[{"name":"A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19140, USA"},{"name":"Penn SRP center, Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"June","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Rabinowitz","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Princeton University, Princeton, NJ 08544, USA"},{"name":"Lewis-Singer Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roddy","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.immuni.2016.01.021","article-title":"Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells","volume":"44","author":"Kawalekar","year":"2016","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.1158\/1078-0432.CCR-13-2627","article-title":"Multifactorial T-cell Hypofunction That Is Reversible Can Limit the Efficacy of Chimeric Antigen Receptor\u2013Transduced Human T cells in Solid Tumors","volume":"20","author":"Moon","year":"2014","journal-title":"Clin. 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