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journal article·2026-03Open access

Metabolic Reprogramming of T Cells by Dual UCP2 and IL‐17 Blockade Enhances Immunity Against Pancreatic Cancer

Chuan‐Teng Liu, Chun‐Chieh Yeh, Tsai‐Chen Wu, Chia‐Hsin Lin, Yi‐Ting Kuo, Yoichiro Iwakura, Yuan‐Ji Day, Charles Drake, Vedran Radojcic, Ying‐Chyi Song, Heng‐Hsiung Wu, Hung‐Rong Yen

Advanced Science· Volume 13· Issue 16
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Source abstract

Abstract

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) remains resistant to immunotherapy due to its immunosuppressive tumor microenvironment (TME) and impaired metabolic fitness of effector T cells. Here, we show that targeting UCP2 reprograms T‐cell metabolism, and that dual blockade with IL‐17 further enhance antitumor responses in PDAC. Pharmacologic UCP2 inhibition with genipin increases IFN‐γ production by CD8⁺ T cells through IL‐12R/STAT4/mTOR signaling and enhanced mitochondrial oxidative phosphorylation, promoting a T‐bet‐driven cytotoxic program. However, UCP2 inhibition alone does not suppress tumor growth. Accordingly, combination with IL‐17 depletion synergistically augments Tc1/Th1 responses, reduces myeloid‐derived suppressor cells (MDSCs), and improves survival across multiple PDAC models, including genetically engineered and orthotopic systems. CD8⁺ T‐cell depletion abrogates these effects. Moreover, UCP2 inhibition enhances IFN‐γ production in patient‐derived PBMCs and tumor‐infiltrating lymphocytes. These findings identify UCP2 as a metabolic checkpoint in cytotoxic T cells and support dual UCP2/IL‐17 blockade as a promising immunotherapeutic strategy for PDAC.
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Research context

OpenAlex topics: Immune cells in cancer · Tryptophan and brain disorders · Immune responses and vaccinations

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Research Center for Traditional Chinese Medicine Department of Medical Research China Medical University Taichung Taiwan

Chinese Medicine Research Center China Medical University Taichung Taiwan

Department of Surgery Organ Transplantation Center China Medical University Hospital Taichung Taiwan

School of Medicine College of Medicine China Medical University Taichung Taiwan

Graduate Institute of Chinese Medicine School of Chinese Medicine College of Chinese Medicine China Medical University Taichung Taiwan

Department of Chinese Medicine Dalin Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Chiayi Taiwan

Research Institute For Biomedical Sciences Tokyo University of Science Tokyo Japan

Department of Anesthesiology Tung's Taichung Metroharbor Hospital Taichung Taiwan

Columbia Center For Translational Immunology Columbia University Irving Medical Center New York USA

Department of Urology Columbia University Irving Medical Center New York USA

Division of Hematology/Oncology Columbia University Irving Medical Center New York USA

Division of Hematology & Hematologic Malignancies Department of Internal Medicine Huntsman Cancer Institute University of Utah Salt Lake City Utah USA

Syndax Pharmaceuticals Waltham Massachusetts USA

Graduate Institute of Integrated Medicine College of Chinese Medicine China Medical University Taichung Taiwan

Research Center For Cancer Biology China Medical University Taichung Taiwan

Drug Development Center China Medical University Taichung Taiwan

The Ph.D. Program for Cancer Biology and Drug Discovery China Medical University and Academia Sinica Taichung Taiwan

Division of Integration of Chinese and Western Medicine, Department of Chinese Medicine China Medical University Hospital Taichung Taiwan

Office of Research and Development Asia University Taichung Taiwan

Funding

China Medical University, Taiwan · Ministry of Science and Technology, Taiwan · China Medical University Hospital

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