2. Academic Validation
  3. Pharmacologic DPP-4 inhibition promotes CD8+ T cell metabolic fitness to enhance anti-tumor activity

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

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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