Diet-microbiome synergy underlies obesity-associated immunotherapy efficacy.

Physiological host factors, such as the gut microbiome and obesity, independently influence anti-tumour immunity and responses to immune checkpoint inhibitors (ICIs) 1 , with high body mass index (BMI) having an unexpected link with greater ICI efficacy 2-6 . However, how these factors interact across diverse dietary contexts remains unclear. Here, using 12 mouse diet models that reflect a spectrum of obesity biology, we characterize diet-driven metabolic, immune and gut microbiota features associated with ICI sensitivity. We find that obesity-associated ICI responses are poorly correlated with metabolic dysfunction and are instead dependent on the diet-gut axis. Obesogenic diets promote a robust and persistent gut microbial ecosystem that is capable of restoring ICI sensitivity following a short-term diet switch or fecal microbiota transplants (FMTs) from non-responder models. Monocolonization of germ-free mice with favourable bacteria such as Lactobacillus johnsonii, together with an obesogenic diet, synergistically promotes tumour regression through an enrichment of microbiota-derived aromatic amino acid metabolites. Moreover, human-to-mouse FMT from donors with a high BMI enhanced ICI efficacy compared with donors with a normal BMI, and an obesogenic diet restored sensitivity following FMT from a non-responder patient. Our study provides insight on epidemiological associations between BMI and ICI efficacy, and suggests that immunomodulatory synergy between diet and the gut microbiota could be leveraged to improve ICI outcomes and FMT interventions.