Obesity-Microbiome Axis Drives Immune Checkpoint Inhibitor Efficacy, New Research Shows

New research reveals that the gut microbiome and diet, rather than metabolic dysfunction, drive the improved responses to immune checkpoint inhibitors (ICIs) associated with obesity, according to a study using 12 mouse diet models. The findings show that obesogenic diets promote a gut microbial ecosystem capable of restoring ICI sensitivity, and human-to-mouse fecal microbiota transplants (FMTs) from donors with a high BMI enhanced ICI efficacy compared with donors with a normal BMI. A separate review of lung cancer studies describes obesity-related systemic inflammation as a crucial regulatory factor in immunotherapy response, including the controversial "obesity paradox" and immune-related adverse events.

The study, which modeled nutritional intake with greater precision than conventional experiments, designed 12 mouse diets reflecting variation in human dietary patterns, including Mediterranean, Japanese, Vegan, American (with and without Aspartame), and Ketogenic diets, plus three diets replacing cellulose with Psyllium, Inulin, or Pectin. After 15 weeks, these diets produced a range of body weights. The researchers found that obesity-associated ICI responses were poorly correlated with metabolic dysfunction and instead depended on the diet–gut axis. Obesogenic diets promoted a robust and persistent gut microbial ecosystem that was capable of restoring ICI sensitivity following a short-term diet switch or FMTs from non-responder models. Monocolonization of germ-free mice with favorable bacteria such as Lactobacillus johnsonii, together with an obesogenic diet, synergistically promoted tumor regression through an enrichment of microbiota-derived aromatic amino acid metabolites. 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. The study suggests that immunomodulatory synergy between diet and the gut microbiota could be leveraged to improve ICI outcomes and FMT interventions.

The review on lung cancer examines the molecular and cellular mechanisms by which obesity-related inflammation influences ICI efficacy through remodeling the tumor microenvironment, altering systemic immune status, and modulating the gut microbiota. It assesses the complex impact of obesity on clinical outcomes of ICI, including the "obesity paradox" phenomenon and immune-related adverse events, particularly endocrine toxicity. The review also surveys novel biomarkers centered around obesity-related inflammatory parameters and body composition, such as circulating adipokines and radiomic features, and their application in integrative predictive models. Based on available evidence, the authors propose multidisciplinary, longitudinal clinical management strategies tailored for obese lung cancer patients and envision novel combination treatment directions targeting the obesity-inflammation axis.