Researchers from the University of Pittsburgh and UPMC Hillman Cancer Center have discovered that sucralose, a widely consumed artificial sweetener, significantly impairs the effectiveness of anti-PD-1 immune checkpoint inhibitor therapy by disrupting the gut microbiome. The study, published in Cancer Discovery, reveals a previously unknown dietary factor that may explain variable immunotherapy responses in cancer patients.
Clinical Evidence Links Sucralose to Poor Treatment Outcomes
The research team surveyed 132 patients with advanced melanoma or non-small cell lung cancer (NSCLC) who had received anti-PD-1 immunotherapy alone or in combination with chemotherapy. Using self-reporting dietary questionnaires, researchers quantified participants' sucralose consumption through tea, coffee, and soft drinks. The results demonstrated that higher levels of sucralose consumption were associated with poorer immunotherapy efficacy across both cancer types.
"We have now found that consumption of artificial sweeteners, especially sucralose, which is hidden in a variety of different drinks and foods, is associated with worse overall response and progression-free response in cancer patients receiving immunotherapy," said Dr. Abby Overacre, lead author and assistant professor in the Department of Immunology at Pitt and UPMC Hillman Cancer Center.
Mechanistic Studies Reveal Gut Microbiome Disruption
To understand the underlying mechanisms, researchers conducted controlled studies using tumor-bearing mice treated with immune checkpoint inhibitors while consuming varying concentrations of sucralose. Consistent with the human survey findings, mice fed higher concentrations of sucralose responded less favorably to anti-PD-1 treatment compared to those on lower sucralose diets, showing increased tumor growth and poorer survival rates.
Analysis of blood, tumor fluid, and stool samples from the mice revealed that higher sucralose consumption led to an increase in specific gut bacteria species that deplete arginine, an amino acid essential for T-cell function and anticancer activity. This depletion compromises the immune system's ability to mount an effective response against cancer cells.
Arginine Supplementation Offers Therapeutic Solution
The study's most promising finding emerged when researchers tested whether the negative effects of sucralose could be reversed. Mice consuming sucralose were given supplements containing arginine or citrulline, which is metabolized into arginine in the body. The supplementation strategy proved highly effective.
"We had mice that were consuming sucralose and then we just supplemented in arginine or citrulline, to boost that amino acid. And what we found is that that worked just as well as if we took them off sucralose completely," Dr. Overacre explained.
The supplemented mice showed restored T-cell function, with immune cells appearing "less exhausted" and better able to kill tumors. This restoration of immune function led to tumor regression and renewed immunotherapy effectiveness.
Clinical Translation and Future Directions
The research team is planning clinical trials to test arginine supplements in human cancer patients, aiming to replicate the T-cell benefits observed in preclinical studies. This approach addresses a practical concern for cancer patients who may find dietary restrictions challenging during treatment.
"It's easy to say, 'Stop drinking diet soda,' but when patients are being treated for cancer, they are already dealing with enough, so asking them to drastically alter their diet may not be realistic," Dr. Overacre noted. "We need to meet patients where they are. That's why it's so exciting that arginine supplementation could be a simple approach to counteract the negative effects of sucralose on immunotherapy."
The current study focused specifically on sucralose, commonly found in yellow packets and various processed foods and beverages. However, the research team plans to expand their investigation to include other artificial sweeteners such as aspartame and saccharin to determine their potential impact on immunotherapy outcomes.
The findings highlight the importance of considering dietary factors in cancer treatment optimization and suggest that simple nutritional interventions could enhance immunotherapy effectiveness without requiring patients to eliminate commonly consumed food additives.
