High sucralose consumption was associated with poorer treatment outcomes in cancer patients.
Three patient cohorts receiving PD-1-based immunotherapy (programmed cell death protein 1) were analyzed, each as part of treatment for:
Sucralose intake was recorded using a dietary questionnaire and classified as “high” (> 0.16 mg/kg/day) or “low/none.”
The cohorts did not differ significantly in terms of baseline data, meaning that the associations observed cannot be explained by demographic or therapeutic factors.
Animal experiments were conducted to clarify possible mechanisms. Mice with transplanted tumors (melanoma and colon cancer model) received sucralose in their drinking water at a dosage corresponding to human intake; at the same time, they were treated with PD-1 inhibitors. The result: under sucralose, the mice were resistant to PD-1 blockade; the tumors grew faster, infiltration by CD8⁺ T cells (a T cell population important for tumor defense) was lower, and survival was shortened.
Sucrose (table sugar) used for comparison did not show any such negative effect.
It was striking that animals from different breeding laboratories reacted differently to sucralose. Only when the mice were kept together—and thus developed a comparable gut microbiome—did these differences disappear. This suggests a mechanism mediated by the microbiome.
In the next step, the authors investigated how sucralose affects the gut microbiome and immune function:
Arginine is particularly important for the proper functioning of T cells: they need this amino acid for their metabolism; arginine is also associated with the activity of cytotoxic T cells against tumor cells.
Based on these findings, the authors supplemented drinking water containing sucralose with either arginine or citrulline—an amino acid that the body can efficiently convert into arginine—in further experiments. Both substances improved T-cell function. Citrulline supplementation was particularly effective: despite sucralose consumption, the response to anti-PD-1 therapy was restored – and was even associated with a survival benefit.
A fecal microbiome transplant from anti-PD-1 responder mice to sucralose-consuming, therapy-resistant animals also normalized the therapeutic response. The effect was strongest when the recipient animals had previously been treated with the antibiotic vancomycin, which is effective against Gram-positive bacteria. This suggests that the removal of sucralose-associated bacteria may be important for renewed response to PD-1-based immunotherapy.
The results show a correlation between high sucralose intake and reduced efficacy of PD-1-based immune checkpoint inhibitors. Animal data show that sucralose alters the gut microbiome and is associated with reduced arginine availability, which impairs T cell function. Since the clinical data are observational findings, prospective studies are needed to further clarify these associations.
However, given the widespread use of calorie-free sweeteners, this work points to a relevant nutrition-related factor that should be taken into account in oncological practice.