The team conducted monocolonization experiments in germ-free mice maintained on a High Fat diet, demonstrating that the presence of L. johnsonii profoundly enhanced anti-tumor responses under immune checkpoint blockade. Importantly, supplementing antibiotic-treated mice on a High Fat diet with L. johnsonii yielded complete tumor clearance, an effect not observed with control PBS gavage. These findings underscore a synergistic interaction whereby both diet and microbiota must align to optimize ICI efficacy.

Extending these insights to human microbiota, fecal microbiota transplantation (FMT) from ICI-refractory lung cancer patients into mice revealed that dietary context can reshape microbial function. Mice on a non-responder Psyllium diet remained insensitive to anti-PD-1 despite identical donor microbiota, whereas those on a High Fat diet regained sensitivity, accompanied by elevated L. johnsonii abundance. This suggests diet can override donor microbiota characteristics to influence therapeutic response.

Metabolomics analyses of serum from diet-treated mice revealed enrichment of aromatic amino acid metabolism pathways, particularly tryptophan and tyrosine derivatives, in ICI responders. Intriguingly, the microbial phenylpropionate metabolite desaminotyrosine (DAT), a tyrosine-derived compound produced by L. johnsonii, emerged as a potent immunomodulator. DAT levels correlated with diet, microbial colonization, and enhanced CD8^+ T cell effector functions, such as increased IFNγ and TNF production.

Ex vivo experiments confirmed that DAT supplementation potentiates CD8^+ T cell responses, especially when combined with microbial products from Psyllium-fed mice. Moreover, in vivo administration of DAT to mice on a non-responder diet restored sensitivity to anti-PD-1 immunotherapy, validating DAT’s functional role in overcoming diet-induced resistance.

Translational relevance was underscored by plasma metabolomics of non-small cell lung cancer (NSCLC) patients undergoing ICI treatment. Responders exhibited elevated levels of tryptophan and phenylpropionate metabolites, including indole-3-lactic acid and a conjugate of DAT, mirroring murine findings. Notably, FMT from high-BMI (obese) human donors conferred greater sensitivity to anti-PD-1 in recipient mice than microbiota from low-BMI individuals.

Collectively, this study uncovers a mechanistic link between obesogenic diets, specific gut microbes, and amino acid-derived metabolites that synergize to enhance cancer immunotherapy. These insights open avenues for dietary and microbial interventions to boost immunotherapy efficacy, particularly in patients with obesity or compromised microbiomes.

Subject of Research: Gut microbiome, diet, and immune checkpoint inhibitor efficacy in cancer therapy.

Article Title: Diet–microbiome synergy underlies obesity-associated immunotherapy efficacy.

Article References:
Desharnais, L., Swaby, A., Messaoudene, M. et al. Diet–microbiome synergy underlies obesity-associated immunotherapy efficacy. Nature (2026). https://doi.org/10.1038/s41586-026-10750-x

DOI: https://doi.org/10.1038/s41586-026-10750-x