Doctors at the University of Pittsburgh and UPMC Hillman Cancer Center have found a link between a common artificial sweetener and the success of cancer immunotherapy.
In a study published in Cancer Discovery, patients who consumed even small amounts of sucralose responded less well to immune checkpoint inhibitor (ICIs) treatments. The pattern was consistent across advanced melanoma, non-small cell lung cancer, and high-risk melanoma after surgery.
The researchers traced the effect to changes in the gut microbiome that reduce levels of arginine, an amino acid critical for T cell function. This could make it harder for the immune system to attack tumors, even when boosted by immunotherapy.
A Subtle but Significant Effect
Immunotherapy works by unleashing the body’s T cells to detect and kill cancer. “When it works, it works very well,” said Abigail Overacre-Delgoffe, an immunologist at Pitt and UPMC Hillman Cancer Center who co-led the study, as per New Scientist. “Patients can be disease-free and go about their lives and live for years.”
But it doesn’t work for everyone. In many cancers, only a minority of patients benefit. The gut microbiome—a vast community of bacteria and other microbes—has emerged as a major factor in determining who responds. Previous research hinted that artificial sweeteners can shift this microbial community. Overacre-Delgoffe and her colleague, oncologist Diwakar Davar, wanted to know whether those shifts mattered for cancer treatment.
They analyzed dietary data from 157 people receiving immune checkpoint inhibitor therapy—91 with advanced melanoma, 41 with advanced non-small cell lung cancer (NSCLC), and 25 with high-risk melanoma after surgery. Before starting treatment, patients filled out detailed diet questionnaires.
The results were striking. Those consuming more than 0.16 milligrams of sucralose per kilogram of body weight a day—just 11 milligrams for a 70-kilogram (155-pound) person—had significantly poorer outcomes.
For advanced melanoma, patients in the low-sucralose group went a median of five months longer without their cancer progressing. In NSCLC, the difference was 11 months. Among patients at high risk of melanoma recurrence, the low-sucralose group stayed cancer-free for six months longer.
“It is about 5% of the [FDA] recommended daily level,” Davar said. “You don’t need a lot to have a relatively bad effect.”
A Closer Look Inside the Body
To understand why, the team turned to mice with melanoma or adenocarcinoma. Mice given sucralose in their water before and during immunotherapy developed larger tumors and died sooner. Their tumors had fewer CD8+ T cells—the immune system’s primary cancer-killers—and those T cells showed signs of exhaustion.
Genetic and metabolic analyses revealed a clue: sucralose-fed mice had a surge in gut bacteria that break down arginine, an amino acid essential for T cell metabolism and function. Arginine levels dropped sharply in their blood, tumors, and stool.
When the researchers supplemented the mice’s water with arginine or citrulline (which the body converts to arginine), the T cells bounced back—and so did the therapy’s effectiveness. Tumors shrank, and survival rates rose to match those of mice not consuming sucralose.
The team also reversed the effect by performing fecal microbiome transplants from healthy, treatment-responsive mice into sucralose-fed ones, suggesting the gut microbes themselves were the key intermediaries.
What This Means for Patients
Sucralose is one of the most widely used non-nutritive sweeteners, marketed as a harmless sugar substitute for people looking to cut calories or control blood sugar. Yet in the context of cancer immunotherapy, even modest consumption may be harmful.
“It’s easy to say, ‘Stop drinking diet soda,’ but patients are already dealing with enough,” Overacre-Delgoffe said. “That’s why it’s so exciting that arginine supplementation could be a simple approach to counteract the negative effects.”
Arginine and citrulline are widely available as over-the-counter supplements. The researchers plan to test citrulline in clinical trials, since it may raise arginine levels more effectively. They also hope to explore whether other sweeteners—like aspartame, saccharin, xylitol, and stevia—have similar effects.
The Bigger Picture
Artificial sweeteners have been under scrutiny for years, with studies linking them to changes in metabolism, gut microbial diversity, and even increased appetite. But this is one of the first to connect them to cancer treatment outcomes—and at such low doses.
The researchers stress that more work is needed before making blanket dietary recommendations. Still, the implications are hard to ignore. For cancer patients on immunotherapy, especially those with melanoma or NSCLC, cutting back on sucralose—or finding ways to offset its effects—could be a low-cost way to tilt the odds in their favor.
