Obesogenic diets and gut bacteria team up to boost cancer immunotherapy in mice

Immune checkpoint inhibitors (ICIs) have transformed cancer care, yet durable responses occur in only a minority of patients. Epidemiological studies associate higher BMI with better ICI outcomes in several cancers, including lung cancer and melanoma. This study explored how diet, metabolic dysfunction and the gut microbiome interact using 12 mouse diet models, focusing primarily on lung cancer.

The diets varied in nutrient sources and included conventional Low Fat, High Fat and Western diets, diets modeled on different dietary patterns, and fiber-substitution diets. After 15 weeks, the researchers characterized body weight, body composition, glucose tolerance, insulin and leptin, and generated a composite metabolic score. Higher scores correlated inversely with circulating CD4+ T cells (r = -0.80, P = 0.0025) and CD8+ T cells (r = -0.59, P = 0.049). In tumor-bearing mice, higher scores correlated with a lower blood lymphoid-to-myeloid ratio (r = -0.82, P = 0.0019), more neutrophils and fewer T cells. HKP1 lung tumor growth did not correlate with body weight or metabolic score.

Bacterial 16S rRNA gene sequencing showed substantial diet-associated differences in gut microbiota. Higher-metabolic-score diets were enriched in several bacterial families, including Lactobacillaceae. Anti-PD-1 sensitivity varied strongly by diet, but across the 12 diets there were no significant associations with body weight, fat mass, glucose intolerance, insulin, leptin or metabolic score. Nevertheless, 4 of 6 obesogenic diets (66.7%) were associated with ICI response, compared with 2 of 6 non-obesogenic diets (33.3%).

The abstract reports additional experiments whose detailed methods and results are not included in the supplied text. Obesogenic diets supported persistent microbial ecosystems capable of restoring ICI sensitivity following short-term diet switches or fecal microbiota transplants 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 enrichment of microbiota-derived aromatic amino acid metabolites.

Also according to the abstract, human-to-mouse transplants from high-BMI donors enhanced ICI efficacy compared with normal-BMI donors. An obesogenic diet restored sensitivity following transplantation from a non-responder patient. These are outcomes in recipient mice, not evidence of benefit in human patients.

The findings suggest that diet-dependent microbial biology contributes to the association between obesity and ICI efficacy, rather than metabolic dysfunction alone explaining it. The work is preclinical, primarily uses a lung cancer model, and includes small treatment groups. The supplied text is truncated, limiting assessment of the later experiments. Nothing here supports adopting a high-fat diet during cancer treatment.