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

## TL;DR

Blocking UCP2 and IL-17 improves T-cell function and fights pancreatic cancer by boosting immune responses.

## Contribution

Dual UCP2 and IL-17 blockade is shown to reprogram T-cell metabolism and enhance anti-tumor immunity in pancreatic cancer.

## Key findings

- UCP2 inhibition with genipin increases IFN-γ production in CD8⁺ T cells via IL-12R/STAT4/mTOR signaling and mitochondrial OXPHOS.
- Combining UCP2 and IL-17 blockade reduces MDSCs and improves survival in PDAC models.
- UCP2 inhibition enhances IFN-γ production in patient-derived PBMCs and tumor-infiltrating lymphocytes.

## 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.

This study demonstrates that dual UCP2/IL‐17 blockade reprograms T‐cell metabolism to overcome PDAC immunosuppression. Genipin‐mediated UCP2 inhibition enhances CD8⁺ T‐cell IFN‐γ via IL‐12R/STAT4/mTOR signaling and mitochondrial OXPHOS. Combined IL‐17 depletion amplifies Tc1/Th1 responses, reduces MDSCs, and prolongs survival in PDAC models, identifying UCP2 as a metabolic checkpoint and therapeutic target.