Journal Club: Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species

Science

3 Sep 2026

Vol 393, Issue 6815

pp. 1036-1044

Editor’s summary

Reactive oxygen species (ROS) have a paradoxical role in cancer. Low to moderate ROS levels can stimulate tumor growth, whereas excessive ROS accumulation triggers oxidative stress and DNA damage. Antioxidant therapies aim to neutralize free radicals and reduce oxidative stress, but clinical trials have not (yet) demonstrated improved cancer survival. Wesolowski et al. report that tumors can turn ROS dependency against the immune system, suppressing T cells and escaping antitumor immunity (see the Perspective by Chandel). Cancer cells secrete antioxidant enzymes, including peroxiredoxin 1 (PRDX1), into the extracellular space, depriving T cells of ROS needed for T cells to attack tumors effectively. Removing PRDX1 from cancer cells restored antitumor immunity and made otherwise resistant tumors sensitive to checkpoint blockade immunotherapy. These results suggest that targeting extracellular redox mechanisms could enhance the efficacy of immunotherapy. —Priscilla N. Kelly

Abstract

Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes. Emerging data suggest that T cells depend on ROS for signal transduction. In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell–mediated antitumor immunity. The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor–driven kinase signaling and effector function. Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses. These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention.