Non-nutritive sweeteners, the gut microbiome, and tumor immunity: evidence hierarchy and a sucralose-centered translational model.

Non-nutritive sweeteners (NNS) are widely used sugar substitutes and constitute heterogeneous dietary and non-dietary exposures. Human gut microbiota findings vary by sweetener identity, purified compound versus commercial formulation, carrier ingredients, dose, duration, host background, and analytical method. Purified compounds and commercial formulations are therefore biologically non-equivalent. A structured narrative search of PubMed, Embase, and the Web of Science Core Collection was conducted from database inception through 17 July 2026 without language restrictions. Evidence was organized by directness to the clinical question and translational distance. Direct human evidence relating NNS exposure to immune checkpoint inhibitor (ICI) outcomes remains observational and sucralose-centered. Experimental evidence for gut microbiota involvement, arginine-related mediation, and reversibility derives mainly from preclinical models; comparable class-wide evidence is lacking. No prospective evidence currently supports NNS-specific dietary modification during immune checkpoint inhibitor therapy. Validation requires prospective, sweetener-specific exposure assessment integrated with gut microbiota, metabolomic, and immune profiling.