Pharmacologic DPP-4 inhibition promotes CD8+ T cell metabolic fitness to enhance anti-tumor activity PMID: 41959339

ADC Targets in Oncology

2026-04-10

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.

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.