Tumor-Derived Antioxidant Protein May Drive Immunotherapy Resistance

Cancer cells may evade immune attack by releasing an antioxidant protein that deprives T cells of the reactive oxygen species (ROS) required for activation, according to research published in Science. The findings identify peroxiredoxin-1 (PRDX1) as a potential therapeutic target for overcoming resistance to cancer immunotherapy.¹

The study challenges the conventional view of ROS as exclusively harmful metabolic byproducts. Although excessive ROS can damage cellular proteins, lipids, and DNA, controlled amounts also function as signaling molecules. The investigators found that T cells depend on this redox signaling to activate and maintain their antitumor functions.¹

Tumors Create an Antioxidant-Rich Microenvironment

Immune checkpoint inhibitors block inhibitory signals such as programmed cell death protein 1 and programmed death ligand 1, allowing T cells to recognize and attack malignant cells. These therapies have changed treatment across numerous tumor types, but many patients either do not respond or eventually develop resistance.²

The new research points to an additional mechanism that may suppress T cells even after conventional immune checkpoints have been blocked.

Investigators analyzed tumor interstitial fluid, which surrounds cells within a tumor, and found that it had strong antioxidant activity. PRDX1 was present at high levels and removed ROS from the tumor microenvironment. This deprived T cells of signals needed for activation, proliferation, cytokine production, and cytotoxic activity.¹

Rather than directly switching off T cells through a receptor-ligand interaction, tumor-secreted PRDX1 altered the chemical conditions surrounding them. The investigators characterized this mechanism as a previously unrecognized “redox checkpoint.”¹

“One of the surprising findings is that antioxidants aren’t always beneficial in the context of cancer,” Robert L. Eil, MD, associate professor of surgery at Oregon Health & Science University and co-senior author of the study, said in a news release. “While reactive oxygen species sound threatening, T cells actually need them to perform their tumor-fighting job.”³

PRDX1 Deletion Restored Antitumor Immunity

To test whether PRDX1 directly contributed to immune evasion, the researchers used CRISPR gene editing to generate cancer cells that could no longer produce the protein. Eliminating tumor-derived PRDX1 increased immune activity and restricted tumor growth across several experimental models.¹

In a melanoma model, tumors lacking PRDX1 were rejected spontaneously by the immune system. PRDX1 deletion also sensitized previously resistant melanoma models to anti–PD-1 and anti–CTLA-4 checkpoint blockade. A mouse hepatocellular carcinoma model demonstrated stronger tumor control when the deletion was paired with immune checkpoint inhibition.^1,4

These experiments suggest that PRDX1 does more than correlate with an immunosuppressive tumor microenvironment. Its removal altered treatment response in preclinical models, providing mechanistic support for targeting the protein therapeutically.

The investigators also evaluated the relevance of the pathway to human cancer. They examined secreted proteins from human cancer cell lines, gene-expression data from thousands of tumors, and PRDX1 concentrations in patient-derived tumor fluid. The analyses indicated that human tumors can release PRDX1 into their surroundings and that increased expression may emerge as tumors undergo immunoediting.¹

During immunoediting, immune pressure shapes tumor evolution by eliminating susceptible cancer cells while allowing variants with effective escape mechanisms to persist. Increased PRDX1 expression could therefore represent an adaptation that helps tumors withstand immune surveillance.

Clinical Translation Remains Unproven

The findings establish a potential target, not an available treatment strategy. The study relied primarily on cell-based and animal models, and no PRDX1-directed therapy has yet demonstrated safety or efficacy in patients. It also remains unclear which tumor types depend most heavily on this pathway or whether PRDX1 levels could predict response to immunotherapy.

Potential approaches include neutralizing extracellular PRDX1, selectively inhibiting its activity within tumors, increasing ROS signaling in the tumor microenvironment, or engineering cellular therapies to withstand antioxidant-mediated suppression. Each strategy would require careful development because disrupting redox balance systemically could damage healthy tissue.^3,4

The research should also not be interpreted as evidence that patients with cancer should discontinue antioxidant-containing foods, prescribed medications, or supplements. Translating a localized tumor mechanism into dietary guidance would go beyond the available evidence. Any supplement changes should be discussed with the oncology care team.

Implications for Oncology Pharmacy

For oncology pharmacists, the study offers an early view of a pathway that could influence future immunotherapy combinations and biomarker development. If PRDX1-targeted treatments reach clinical testing, pharmacists will be positioned to assess dosing, interactions, toxicity, and how redox-modifying agents integrate with checkpoint inhibitors or engineered T-cell therapies.

By identifying tumor-derived antioxidants as active mediators of immune escape, the study broadens the understanding of immunotherapy resistance beyond conventional surface checkpoints. Further research must now determine whether blocking this redox checkpoint can safely restore antitumor immunity in patients.

REFERENCES

1. Wesolowski AJ, Pillay AM, et al. Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species. Science. 2026;393(6815):1036-1044. doi:10.1126/science.adz8203

2. National Cancer Institute. Immune checkpoint inhibitors. Last Reviewed April 7, 2022. Accessed September 4, 2026. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors

3. Yeager A. Cancer cells use antioxidant protein to suppress T cells, resist immunotherapy, study finds. Oregon Health & Science University. Published September 3, 2026. Accessed September 4, 2026. https://news.ohsu.edu/2026/09/03/cancer-cells-use-antioxidant-protein-to-suppress-t-cells-resist-immunotherapy-study-finds

4. Cancer cells release antioxidants to prevent immune cells from destroying them. News release. University of Cambridge. Published September 3, 2026. Accessed September 4, 2026. https://www.cam.ac.uk/research/news/cancer-cells-release-antioxidants-to-prevent-immune-cells-from-destroying-them