美国匹兹堡大学Greg M. Delgoffe小组的最新研究提出了氧化应激诱导的端粒不稳定在癌症中驱动T细胞功能障碍。相关论文于2025年9月9日发表在《免疫学》杂志上。

课题组研究人员发现，癌症中的功能失调T细胞并不含有表明复制衰老的短端粒，而是含有受损的端粒，课题组研究人员假设这是由氧化应激引起的。化学光遗传诱导高度定位的线粒体或端粒活性氧（ROS）以光敏剂为主题，引导端粒DNA损伤的积累，驱动端粒的脆弱性。端粒损伤足以驱动T细胞的功能失调状态，显示细胞因子生产能力下降。将ROS清除剂GPX1直接定位到端粒可以降低肿瘤中端粒的脆弱性，并改善治疗性T细胞的功能。通过端粒靶向抗氧化剂的表达来保护端粒，可以保护TME中的T细胞功能，并对细胞治疗产生更好的反应。

据了解，肿瘤微环境（TME）施加的免疫和代谢压力足以使免疫细胞分化进入功能失调状态。源自线粒体的氧化应激可引起DNA损伤，最明显的是端粒。

附：英文原文

Title: Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer

Author: Dayana B. Rivadeneira, Sanjana Thosar, Kevin Quann, William G. Gunn, Victoria G. Dean, Bingxian Xie, Angelina Parise, Andrew C. McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P. Barnes, Marcel P. Bruchez, Patricia L. Opresko, Greg M. Delgoffe

Issue&Volume: 2025-09-09

Abstract: The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.

DOI: 10.1016/j.immuni.2025.08.008

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00371-1