Abstract 1338: DPP-4: A CD8+ T cell metabolic checkpoint and cancer immunotherapy target.

Abstract Exhaustion of CD8+ T cells in the tumor microenvironment is intertwined with metabolic dysfunction. Thus, metabolic reinvigoration of T cells is a promising cancer immunotherapy strategy. Here, we identify dipeptidyl peptidase 4 (DPP-4) as an immune checkpoint molecule driving the hypometabolic state of exhausted CD8+ T cells. We found that DPP-4 is highly expressed by CD8+ T cells infiltrating brain tumors, and its expression levels increase with terminal exhaustion. Pharmacological inhibition of DPP-4 with the FDA-approved sitagliptin, which is used for the management of type II diabetes, transcriptionally and metabolically reprogrammed CD8+ T cells to upregulate lymphocyte activation pathways and enhance mitochondrial spare respiratory capacity. Functionally, DPP-4 inhibition increased proliferation, antigen-specific cancer cell killing capability, and cytotoxic mediator production of mouse CD8+ T cells and IL13Ra2 CAR T cells in vitro. Mechanistically, inhibiting DPP-4 upregulated glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle. Pharmacological inhibition of GAD1 abrogated sitagliptin-mediated T cell proliferation and metabolic reprograming of mouse and human CD8+ T cells, underscoring a new role for this enzyme in T cell functional regulation. Systemic inhibition of DPP-4 prolonged survival in preclinical glioblastoma (GBM) models in a CD8+ T cell-dependent manner. Furthermore, retrospective analysis indicated that GBM patients on DPP-4 inhibitors, gliptins, have better outcomes compared to those receive standard of care alone or in combination with metformin. Collectively, our results support repurposing the clinically used and well-tolerated class of DPP-4 inhibitors to enhance cancer immunotherapy responses. Citation Format: Oriana Teran Pumar, Durga Prasad Gannamedi Hinder, Dylan Harwood, Julia Benedetti, Christine Ballard, Erika Ciervo, Clara Lopez Ruiz, Christine Rafie, Jonathan Mitchell, Brandon Emanuel Leon, Pedro Henrique Assenza Tavares Coroa, Bruno Colon, Michele Ceccarelli, Quinn T. Ostrom, Zev Binder, Dionysios Watson, Erietta Stelekati, Bjarne Winther Kristensen, David Lombard, Defne Bayik. DPP-4: A CD8+ T cell metabolic checkpoint and cancer immunotherapy target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1338.