Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer
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.
Authors
- Patricia L. Opresko (ORCID: https://orcid.org/0000-0002-6470-2189)
- Angelina M. Parise (ORCID: https://orcid.org/0000-0003-0207-2510)
- Bingxian Xie (ORCID: https://orcid.org/0000-0001-9816-2670)
- Dayana B. Rivadeneira (ORCID: https://orcid.org/0000-0001-9483-7036)
- Sanjana Thosar (ORCID: https://orcid.org/0000-0001-5894-4176)
- Victoria Dean (ORCID: https://orcid.org/0009-0002-9136-3917)
- Konstantinos Lontos (ORCID: https://orcid.org/0000-0003-0216-3818)
- William Gunn (ORCID: https://orcid.org/0000-0002-3555-2054)
- Marcel P. Bruchez (ORCID: https://orcid.org/0000-0002-7370-4848)
- Ryan Barnes (ORCID: https://orcid.org/0000-0003-0122-5773)
- Kevin Quann (ORCID: https://orcid.org/0000-0003-2213-3771)
- Kellie Spahr (ORCID: https://orcid.org/0000-0002-4119-4994)
- Greg M. Delgoffe (ORCID: https://orcid.org/0000-0002-2957-8135)
- A McGovern (ORCID: https://orcid.org/0009-0001-1566-557X)
Institutions
- University of Pittsburgh (US)
- The University of Kansas Cancer Center (US)
- University of Kansas Medical Center (US)
- Carnegie Mellon University (US)
Publication Details
- Journal
- Immunity
- Published
- 2025-09-10
- DOI
- https://doi.org/10.1016/j.immuni.2025.08.008
- Citations
- 14
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 16.30
Funders
- Cancer Research Institute
- University of Pittsburgh
- National Institutes of Health