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

Area of Science:

• Immunology
• Metabolic pathways
• Cancer research

Background:

• Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to immunotherapy.
• The tumor microenvironment (TME) and T-cell metabolic dysfunction contribute to this resistance.

Purpose of the Study:

• To investigate the role of UCP2 in T-cell metabolism and its potential as an immunotherapeutic target in PDAC.
• To evaluate the efficacy of dual blockade of UCP2 and IL-17 in enhancing anti-tumor responses.

Main Methods:

• Pharmacologic UCP2 inhibition using genipin.
• Assessment of T-cell metabolism, cytokine production (IFN-γ), and signaling pathways (IL-12R/STAT4/mTOR).
• Evaluation of combination therapy with IL-17 depletion in preclinical PDAC models and patient-derived cells.

Main Results:

• UCP2 inhibition enhanced CD8+ T-cell effector functions, including IFN-γ production and oxidative phosphorylation.
• Dual UCP2 and IL-17 blockade synergistically boosted anti-tumor immunity, reduced myeloid-derived suppressor cells (MDSCs), and improved survival.
• UCP2 inhibition increased IFN-γ production in patient-derived immune cells.

Conclusions:

• UCP2 acts as a metabolic checkpoint in cytotoxic T cells.
• Combined UCP2 inhibition and IL-17 blockade represent a promising immunotherapeutic strategy for PDAC.