CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Metabolic Reprogramming of T Cells by Dual UCP2 and IL-17 Blockade Enhances Immunity Against Pancreatic Cancer.
Metabolic Reprogramming of T Cells by Dual UCP2 and IL-17 Blockade Enhances Immunity Against Pancreatic Cancer.
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胰腺导管腺癌（PDAC）因其免疫抑制性肿瘤微环境（TME）和效应T细胞代谢适应性受损，仍然对免疫治疗耐药。在此，我们表明靶向UCP2可重编程T细胞代谢，并且与IL-17双重阻断可进一步增强PDAC中的抗肿瘤反应。使用genipin进行药理学UCP2抑制，通过IL-12R/STAT4/mTOR信号通路增加CD8⁺ T细胞产生IFN-γ，并增强线粒体氧化磷酸化，促进T-bet驱动的细胞毒性程序。
然而，单独抑制UCP2并不能抑制肿瘤生长。因此，与IL-17清除联合可协同增强Tc1/Th1反应，减少髓源性抑制细胞（MDSCs），并改善多种PDAC模型（包括基因工程和原位系统）中的生存。清除CD8⁺ T细胞可消除这些效应。
此外，UCP2抑制可增强患者来源的PBMCs和TIL（肿瘤浸润淋巴细胞）中的IFN-γ产生。这些发现将UCP2确定为细胞毒性T细胞中的代谢检查点，并支持将UCP2/IL-17双重阻断作为PDAC的一种有前景的免疫治疗策略。
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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