Pharmacologic DPP-4 inhibition promotes CD8+ T cell metabolic fitness to enhance anti-tumor activity

  • bioRxiv. 2026 Apr 3:2026.03.31.715681. doi: 10.64898/2026.03.31.715681.
Oriana Y Teran Pumar  1  2 ,  Elton L VanNoy  3 ,  Abigail Haffey  3 ,  Durga Prasad Gannamedi  2  4 ,  Christine Isabelle Rafie  5 ,  Dylan Scott Lykke Harwood  6  7 ,  Julia R Benedetti  8 ,  Christine Ann Pittman Ballard  8 ,  Erika Ciervo  2 ,  Pedro Henrique Assenza Tavares Coroa  9 ,  Payal Grover  10 ,  Brandon Emanuel León  1 ,  Jonathan Mitchell  1  9 ,  Asmita Pathak  1  2 ,  Bruno Colon  1 ,  Lyenne El Ghorayeb  11 ,  Laura O'Sullivan  10 ,  Venu Venkatarame Gowda Saralamma  2  9 ,  Clara Lopez Ruiz  9 ,  Natasha Khatwani  4 ,  Surinder Kumar  2  4 ,  Priyamvada Rai  2  9 ,  Jonathan Schatz  2  9 ,  Ashish Shah  2  12 ,  Zev A Binder  10 ,  Michele Ceccarelli  2 ,  Quinn T Ostrom  8  13  14 ,  Bjarne Winther Kristensen  6  7 ,  Erietta Stelekati  2  5 ,  Dionysios C Watson  2  15 ,  David B Lombard  2  4  16 ,  Dalia Haydar  3  11 ,  Defne Bayik  1  2
Affiliations
  • 1. Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 2. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
  • 3. George Washington University, School of Medicine and Health Sciences, USA.
  • 4. Department of Pathology and Laboratory Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 5. Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 6. The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • 7. Department of Clinical Medicine and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
  • 8. Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
  • 9. Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 10. Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
  • 11. Children's National Research Institute, USA.
  • 12. Department of Neurosurgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 13. The Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Durham, NC, USA.
  • 14. Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
  • 15. Medical Oncology Division, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 16. Miami Veterans Affairs Geriatric Research Education and Clinical Center (GRECC), Bruce W. Carter VA Medical Center, Miami, FL, USA.
PMID: 41959339 DOI: 10.64898/2026.03.31.715681
Abstract

Metabolic dysfunction is a hallmark of CD8+ T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8+ T cells via metabolic reprogramming. Here, we identify Dipeptidyl Peptidase 4 (DPP-4) as a previously unknown regulator of CD8+ T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8+ T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8+ 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+ T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse Glioblastoma (GBM) models prolongs survival in a CD8+ 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+ T cell responses.

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