Harnessing the Microbiome in Cancer Immunotherapy: Regulation, Prediction, and Therapeutic Targeting.

This review frames cancer as a disease of the human “metaorganism,” emphasizing that host cells and the microbiome jointly shape cancer risk, progression, and treatment response.

Key points:

• • Microbiome–cancer biology: Commensal microorganisms, mainly at epithelial barriers, influence:

  • • Genome stability and tissue organization
  • • Chronic inflammation and immune tone
  • • Tumor initiation, promotion, and metastasis

  These effects can be pro- or antitumor depending on context and microbial composition.

• • Impact on immunotherapy:

  • • Specific microbiome features are associated with response or resistance to immune checkpoint inhibitors.
  • • Machine learning models using microbiome data show moderate ability to predict clinical response and immune-related adverse events, suggesting potential for biomarker development but not yet clinical-grade performance.

• • Fecal microbiota transplantation (FMT) in cancer care:

  • • Single-arm and randomized studies demonstrate that FMT from immunotherapy responders or healthy donors, combined with PD-1 blockade, can:
    • • Convert some PD-1–refractory patients into responders
    • • Enhance outcomes as a first-line strategy in selected settings
  • • These trials support a causal role of the microbiome in modulating immunotherapy efficacy.

• • Clinical opportunities and challenges:

  • • Opportunities: Microbiome-based biomarkers, microbiome modulation (diet, probiotics, FMT, defined consortia) to improve efficacy and reduce toxicity of immunotherapy.
  • • Challenges: Interindividual variability, lack of standardization in microbiome profiling and FMT protocols, safety concerns, regulatory issues, and the need for larger, controlled trials.

Overall, the article positions microbiome manipulation as a promising adjunct to immunotherapy but emphasizes that translation into routine oncology practice requires rigorous validation and standardized approaches.