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.