Oxidative stress induced telomere instability/damage drives T cell dysfunction in cancer

The tumor microenvironment imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional fates like exhaustion. Our data show that dysfunctional T cells in cancer do not harbor short telomeres indicative of replicative senescence, but rather harbor damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of localized mitochondrial or telomeric reactive oxygen species (ROS) using a novel photosensitizer caused DNA damage at telomeres and was sufficient to drive a dysfunctional state in newly activated T cells, with 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 protein may preserve T cell function in the tumor microenvironment and drive superior responses to adoptive cell therapies.