New data may ignite debate about whether artificial sweeteners can alter the gut microbiome and, in turn, reduce how effective immunotherapy is in patients with cancer.

A study in Cancer Discovery found that sucralose (Splenda) is associated with reduced efficacy of checkpoint inhibitor therapy in patients with cancer. In tumor-bearing mice, sucralose exposure was also linked to alterations in the gut microbiome, lower levels of microbiota-accessible arginine, and changes in T-cell function consistent with impaired antitumor immunity, in experiments conducted as part of the research.

Although this is the first study to link sucralose with cancer treatment response, prior research has suggested that the microbiome can shape immunotherapy outcomes, while other artificial sweeteners have been shown to disrupt gut flora.

Together, these findings raise the following clinical questions: “Should patients on immunotherapy avoid sucralose?” And “do other artificial sweeteners pose similar risks?”

Evidence in Humans and Mice

In the new Cancer Discovery study, Kristin Morder, MS, of UPMC Hillman Cancer Center, Pittsburgh, and colleagues assessed dietary intake across more than 150 patients receiving PD-1 inhibitors for advanced melanoma, non-small cell lung cancer (NSCLC), or high-risk resectable melanoma.

Among patients with advanced melanoma, high sucralose consumers (> 0.16 mg/kg/d or about one packet daily for a 70-kg person) had an objective response rate (ORR) of 27% vs 53% for lower consumers (P = .037), while median progression-free survival (PFS) was 8.0 vs 13.0 months (hazard ratio [HR], 2.23; P = .037). In NSCLC, the ORR was 16% vs 60% (P = .0075), with median PFS of 7.0 vs 18.0 months (HR, 2.78; P = .034). In the resectable melanoma cohort, major pathologic responses occurred in 12% of high consumers compared with 49% of lower consumers (P = .044), and median relapse-free survival was 19.0 vs 25.0 months (HR, 6.69; P = .012).

To search for possible mechanisms that might explain these differences, the investigators performed metagenomic sequencing and metabolomic profiling of stool from sucralose-fed, tumor-bearing mice receiving immune checkpoint inhibitor therapy.

The analyses showed enrichment of microbial pathways for arginine degradation, along with significantly reduced levels of arginine and citrulline in stool. Arginine depletion was also confirmed in serum and tumor interstitial fluid and was associated with reduced expression of the amino acid transporter Slc7a3, which normally mediates arginine uptake. This depletion coincided with features of T-cell exhaustion in the tumor microenvironment, which the investigators attributed to arginine’s roles in T-cell metabolism.

Next, mice were given sucralose-containing water supplemented with arginine or citrulline (an arginine-related metabolite). In these experiments, supplementation was associated with restoration of arginine levels and signs of improved T-cell activity, including higher interferon-γ production in CD4+ and CD8+ T cells. Citrulline supplementation, specifically, coincided with restored responses to PD-1 therapy and longer survival, even while mice continued to receive sucralose.

“Our work suggests that increased sucralose consumption is associated with poorer efficacy of immune checkpoint inhibitor-based immunotherapy in melanoma and NSCLC patients and sheds light on how sucralose may impact T-cell functionality and immune checkpoint inhibitor efficacy in a gut microbiome-centric fashion,” Morder and colleagues wrote, in their paper. “Future prospective studies will be necessary to assess potential causation of sucralose in driving immunotherapy resistance as well as to determine how other demographic factors, including location and food access, may impact overall responses.”

Khalid Shah, PhD, professor at Harvard Medical School and director of the Center for Stem Cell and Translational Immunotherapy at Brigham and Women’s Hospital, Boston, said the study’s combination of patient associations and mouse mechanistic data provides an important signal.

“From a translational research perspective, the published study from Morder et al clearly indicates a role of sucralose in reducing immunotherapy effectiveness via gut microbiome shifts and arginine depletion, leading to T-cell exhaustion,” Shah told Medscape Medical News. “Although this study presents an extensive dataset in mouse tumor models with clinical data echoing these findings in cancer patients, more studies are needed to show the link between artificial sweeteners and immunotherapy.”

Other Non-Nutritive Sweeteners and the Microbiome

Findings related to other non-nutritive sweeteners in the Cancer Discovery analysis appeared to be less concerning. The high intake of acesulfame showed some reduction in immunotherapy efficacy but results were inconsistent. Aspartame and saccharin did not significantly affect immunotherapy response, though intake levels were relatively low, and the study was not powered to rule out smaller effects.

This kind of variability has been reported by previous studies investigating the potential effects of non-nutritive sweeteners on the microbiome. For example, in 2022, a randomized controlled trial, compared consumption of sucralose, saccharin, aspartame, and stevia in 120 healthy adults who previously abstained from these additives. Sucralose and saccharin significantly impaired glucose tolerance and altered the microbiome, while aspartame and stevia had more variable or negligible effects.

“It is clear that non-nutritive sweeteners can alter the microbiome and have detrimental impacts on health in at least some individuals; however, the frequency of this occurrence remains unclear,” said Jotham Suez, PhD, assistant professor of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health, Baltimore, who led the Cell trial.

Suez noted that fewer than 10 human studies have directly examined how consumption of sweeteners is related to the microbiome. These include both observational cohort studies and small randomized interventional trials. Taken together, he said, the evidence points to a plausible link between non-nutritive sweeteners, microbiome alterations, and downstream health effects, though results vary depending on the compound and the individual.

Caution and Clinical Implications

Variability across studies may be partly explained by methodological challenges, according to Arielle Elkrief, MD, assistant professor of oncology and co-director of the microbiome center at the University of Montreal in Montreal, Quebec, Canada.

“Diet and food additives are often hidden exposures that can confound results,” Elkrief told Medscape Medical News. “Measuring intake precisely is hard, and the microbiome can be sensitive to these seemingly small additions in diet.”

Suez also pointed out this challenge, noting that “consumers of non-nutritive sweeteners often consume more than one type of sweetener, and therefore it is difficult to isolate the contribution of a single type of sweetener.”

Despite these limitations, Elkrief said the overall body of evidence is strong enough to guide clinical conversations between oncologists and patients receiving immunotherapy.

“I’d advise caution against sweeteners and additives based on these data,” she said. “The preclinical rationale is strong. That said, we would welcome prospective clinical data to confirm these findings.”

Shah, who was not involved in the new research, agreed, suggesting that it “seems very logical that immunotherapy patients could benefit from avoiding artificial sweeteners.”

Suez, however, maintained a more neutral stance.

“This is the first study to suggest that consumption of non-nutritive sweeteners can impact immunotherapy efficacy,” he said. “The preclinical data are compelling, but more work is needed to determine whether the causal link between sucralose and reduced immunotherapy response is applicable in humans.”

Specifically, Suez called for data showing that microbiome transplants from human sucralose consumers induce immunotherapy resistance in mice, while transplants from non-consumers do not. These findings “would be helpful to strengthen this link and support the hypothesis that the mechanism shown in mice is also the reason for reduced immunotherapy responsiveness in humans.”

Until such data are available, “advice to patients should balance the benefits and risks,” he said.

Turning the Tide

While the new sucralose data point to the risks of dietary exposures, recent reviews by Elkrief and Shah highlight a complementary line of research: leveraging the microbiome to enhance immunotherapy.

In a recent Nature Reviews Drug Discovery article, Elkrief and colleagues described how interventions like fecal microbiota transplantation, probiotics, prebiotics, and diet modifications are being explored to strengthen immune responses to checkpoint inhibitors.

Writing in Cells, Shah and colleagues explored the microbiome’s role in shaping outcomes with cellular immunotherapies such as CAR-T therapy, noting that certain bacterial taxa and microbiota-derived metabolites are linked to improved efficacy and reduced toxicities.

“The gut microbiome is a dynamic ecosystem that can either fuel or dampen antitumor immunity,” said Elkrief, who also was not an author of the Cancer Discovery paper. “The next phase of the field will be about learning how to deliberately tune this ecosystem.”

To this end, she said, patients must be protected from exposure to elements that push the microbiome into an immunosuppressive state, like sucralose. Simultaneously, “targeted strategies” are needed “to shift the balance back toward enhanced antitumor immunity, whether through defined bacterial consortia or live biotherapeutic products, nutrition interventions, or metabolite supplementation.”

This study was supported by the National Institutes of Health/National Cancer Institute Cancer Center and Break Through Cancer Foundation. The investigators disclosed relationships with AstraZeneca, Biom Up, BioNTech SE, and others. Shah and Suez disclosed no conflicts of interest. Elkrief disclosed relationships with Kanvas Bioscience, GMT Science, Merck, and others.