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

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.