Study links common sweetener sucralose to reduced immunotherapy effectiveness in early research

A common artificial sweetener, sucralose, was associated with weaker responses to anti-PD1 immunotherapy and poorer survival in a small observational study of cancer patients, and laboratory experiments in mice suggest a possible biological mechanism, researchers reported.

Investigators at the University of Pittsburgh and UPMC Hillman Cancer Center analyzed dietary data from 132 patients being treated for melanoma or non‑small cell lung cancer who were receiving anti‑PD1 therapy, alone or in combination with chemotherapy. Patients who reported higher consumption of sucralose had worse clinical responses and shorter survival than those reporting lower intake, the team reported in the journal Cancer Discovery.

Laboratory studies accompanying the clinical observations found that mice fed sucralose developed shifts in the gut microbiome associated with reduced levels of the amino acid arginine. Arginine is important for T‑cell function, and in the mouse experiments depleted arginine was linked to impaired T‑cell activity and diminished benefit from checkpoint inhibitor therapy. Supplementing arginine in the mouse model largely reversed the negative effect of sucralose on immunotherapy efficacy.

"We found that sucralose impeded the effectiveness of immunotherapies across a range of cancer types, stages and treatment modalities," said senior author Diwakar Davar, an associate professor of medicine at Pitt and a medical oncologist at UPMC Hillman Cancer Center. Lead author Abby Overacre, an assistant professor in Pitt’s Department of Immunology, said arginine supplementation could be a practical strategy to offset the observed effects: "It’s so exciting that arginine supplementation could be a simple approach to counteract the negative effects of sucralose on immunotherapy."

The investigators emphasized that the human component of the study was observational and relied on self‑reported dietary questionnaires, which are subject to misreporting and bias. In a statement provided through industry channels, the Calorie Control Council noted that the study combines animal research that cannot be directly applied to humans with a small, self‑reported human dataset and reiterated that regulatory authorities, including the U.S. Food and Drug Administration, have repeatedly affirmed sucralose’s safety.

Researchers said the findings do not yet warrant broad dietary recommendations for patients undergoing cancer treatment and that clinical guidance should come from treating health‑care teams. The study’s authors plan a clinical trial to test whether arginine supplementation can improve immunotherapy responses in people who consume high amounts of sucralose, and they intend to investigate whether other sugar substitutes have similar effects.

The research received support from the National Institutes of Health, the Damon Runyon Cancer Research Foundation and Gateway for Cancer Research. The published report calls for additional, larger prospective studies to confirm the association in humans and to determine whether targeted nutritional interventions can safely and reliably improve immunotherapy outcomes.

Manufacturers of sucralose‑containing products were contacted for comment. The investigators and funders cautioned that further research is needed before practice changes are recommended, and patients are advised to consult their oncology teams about any diet changes or supplement use during treatment.

Additional laboratory and clinical work is under way to clarify the mechanism linking sucralose, microbiome alterations and arginine depletion, and to test whether restoring arginine levels improves T‑cell function and treatment efficacy in patients receiving checkpoint inhibitors.