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Microbial metabolic pathways, not specific bacteria, predict immunotherapy response. The methylerythritol 4-phosphate (MEP) pathway enhances antitumor immunity, while riboflavin synthesis hinders it, impacting patient survival.

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Area of Science:

  • Microbiome research
  • Immunotherapy
  • Metabolic pathways

Background:

  • Specific bacteria linked to immunotherapy efficacy lack consistency across studies.
  • Mechanisms of microbiome influence on immune checkpoint blockade (ICB) response remain unclear.

Purpose of the Study:

  • To investigate the functional capacity of the microbiome in predicting ICB response.
  • To elucidate the mechanisms of microbiome-mediated immune modulation in cancer.

Main Methods:

  • Analysis of pan-cancer metagenomics data from ICB-treated patients.
  • Identification of microbial metabolic pathways associated with ICB response.
  • In vitro studies using patient-derived tumor organoids and gut metabolomics.

Main Results:

  • Community-level microbial metabolic pathways are stable and predict ICB response.
  • The methylerythritol 4-phosphate (MEP) pathway correlates with response and enhances Vδ2 T cell antitumor activity.
  • Riboflavin synthesis correlates with resistance, suppressing T cell responses and linking high riboflavin levels to worse survival.

Conclusions:

  • Microbial metabolic pathways, rather than specific species, are key predictors of ICB efficacy.
  • Metabolite-mediated cross-talk between the microbiome and immune cells influences cancer immunotherapy outcomes.