Sucralose consumption ablates cancer immunotherapy response through microbiome disruption.

Abstract Gut microbiota composition is directly associated with response to immunotherapies in cancer. How the diet impacts the gut microbiota and downstream immune responses to cancer remains unclear. Here, we show that consumption of a common non-nutritive sweetener, sucralose, modifies microbiome composition, restricts T cell metabolism and function, and limits immunotherapy response in preclinical models of cancer and advanced cancer patients treated with anti-PD-1 based immune checkpoint inhibitors (ICIs). Sucralose consumption is associated with a reduction in microbiota-accessible arginine, and amino acid supplementation or fecal microbiome transfer (FMT) from anti-PD-1 responder mice completely restores T cell function and immunotherapy response. Overall, sucralose consumption destabilizes the gut microbiota, resulting in compromised T cell function and ablated ICI response in cancer.