{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T17:17:50Z","timestamp":1775495870086,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,3]]},"group-title":"Immunology","reference-count":105,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Metabolic dysfunction is a hallmark of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell responses.\n                <\/jats:p>","DOI":"10.64898\/2026.03.31.715681","type":"posted-content","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T20:15:27Z","timestamp":1775247327000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacologic DPP-4 inhibition promotes CD8\u207a T cell metabolic fitness to enhance anti-tumor activity"],"prefix":"10.64898","author":[{"given":"Oriana Y.","family":"Teran Pumar","sequence":"first","affiliation":[{"name":"Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elton L","family":"VanNoy","sequence":"additional","affiliation":[{"name":"George Washington University, School of Medicine and Health Sciences, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail","family":"Haffey","sequence":"additional","affiliation":[{"name":"George Washington University, School of Medicine and Health Sciences, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Durga Prasad","family":"Gannamedi","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA"},{"name":"Department of Pathology and Laboratory Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine Isabelle","family":"Rafie","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan Scott","family":"Lykke Harwood","sequence":"additional","affiliation":[{"name":"The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia R.","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine Ann","family":"Pittman Ballard","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Ciervo","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Henrique","family":"Assenza Tavares Coroa","sequence":"additional","affiliation":[{"name":"Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Payal","family":"Grover","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon Emanuel","family":"Le\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA"},{"name":"Leonard M. 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