Summary: Morder, Nguyen, Wilfahrt, and colleagues report that nonnutritive sweeteners impair the efficacy of anti–PD-1 therapy through mechanisms that involve regulation of microbiota and metabolites. Their findings underscore the clinical relevance of long-term lifestyle interventions, such as limiting daily intake of nonnutritive sweeteners, across multiple cancer types. See related article by Morder et al., p. 2278