Researchers publishing in Science have discovered that cancer cells release an antioxidant enzyme called PRDX1 into surrounding fluid, creating a hostile microenvironment that neutralizes the reactive oxygen species cancer-fighting T cells need to activate and attack tumors, offering a new target for improving immunotherapy.
For decades, medical science has cast free radicals and other reactive oxygen species primarily as harmful molecules. Researchers have long associated these unstable molecules, which include hydrogen peroxide, with DNA damage, genomic instability, and cancer-promoting signaling. That traditional framework helped fuel interest in antioxidant supplements as a way to prevent or treat cancer, despite large clinical trials repeatedly failing to show a benefit and occasionally revealing worse patient outcomes. A new study co-led by Oregon Health & Science University and the University of Cambridge turns that conventional wisdom on its head, revealing that while reactive oxygen species sound threatening, immune system defenders actually require small amounts of them to perform their jobs.
How PRDX1 Shuts Down Antitumor Immunity
The investigation, published in the journal Science, centers on the liquid surrounding cells within a tumor. By analyzing this tumor interstitial fluid, researchers discovered potent antioxidant activity driven by high levels of an enzyme known as peroxiredoxin-1, or PRDX1. Cancer cells release this enzyme into their immediate surroundings, crafting an antioxidant-rich ecosystem that chemically “smothers” approaching immune cells. The findings reveal what researchers describe as a previously unrecognized redox checkpoint
that tumors exploit to escape immune attack.
“One of the surprising findings is that antioxidants aren’t always beneficial in the context of cancer. While reactive oxygen species sound threatening, T cells actually need them to perform their tumor-fighting job. What we found is that tumors can exploit the T cell’s dependency by removing the reactive oxygen species the immune system depends on.”
Robert L. Eil, M.D., co-senior author of the study, associate professor of surgery in the OHSU School of Medicine, and member of the OHSU Knight Cancer Institute, via OHSU News
T cells rely on reactive oxygen species as part of the molecular signaling that switches on their cancer-killing functions. When extracellular PRDX1 floods the tumor microenvironment, it strips away these vital molecules. Alexander J. Wesolowski, a researcher in the Department of Pathology at the University of Cambridge and first author of the study, noted that we are increasingly understanding that ROS have important functions within cells, and T cells require them to activate.
When researchers added extracellular PRDX1 directly to T cells in experimental setups, it reduced their reactive oxygen species levels and disrupted T-cell receptor signaling.
CRISPR Gene Editing and Human Tumor Analysis
To confirm whether PRDX1 directly contributes to tumor immune evasion, the research team turned to advanced genetic tools. Using CRISPR gene-editing technology, investigators engineered cancer cells that could no longer produce the antioxidant protein. Removing PRDX1 enhanced immune activity and reduced tumor growth across multiple experimental models.
The study also addressed whether this immune-evasion tactic translates to human biology. The team examined published datasets from human cancer cell lines, analyzed gene activity across thousands of human tumors, and measured PRDX1 in fluid collected directly from patient tumors. Across all three investigative approaches, the team found evidence that human cancers also release PRDX1 into their surroundings to suppress T-cell activity.
Implications for Future Immunotherapy Design
The discovery helps explain a long-standing mystery in cancer research: many cancers either do not respond to immunotherapy or eventually develop resistance. The study indicates that cancer cells increase PRDX1 expression during immunoediting, an evolutionary process where tumors evolve under pressure from the immune system and acquire characteristics that help them escape immune attack.
While these therapeutic strategies remain preclinical, the identification of the redox checkpoint points toward several distinct avenues for intervention.
