Genome mining of the tumor microbiome reveals biosynthetic diversity and potential pathology-modulating metabolites

Human tumor-associated microbes - the tumor microbiome - have demonstrated an increasingly important role in human health due to their relevance to cancer progression and treatment response. While the metabolism at the host-microbiota interface, such as in the human gut, has been extensively investigated in recent years, the specialized metabolites from the tumor microbiome remain uncharted territory. To address this knowledge gap, we report a survey of the biosynthetic potential of the human tumor microbiome. Utilizing high-quality microbial metagenome-assembled genomes from 3,526 human tumor tissue samples, we identify 528 biosynthetic gene clusters with the potential to encode specialized metabolites relevant to tumor pathology. We reveal that the tumor microbiome encodes known and unknown metabolites spanning multiple biosynthetic classes. From this diverse biosynthetic landscape, we express a conserved family of biosynthetic genes from the genus Fusobacterium, which has a well-established role in cancer, and discover distinct families of long-chain fatty acyl amides. We subsequently find that one of these fatty acyl amides, oleoyl γ-aminobutyric acid, has immunomodulatory and G-protein-coupled receptor partial agonist activities, potentially supporting the influence of Fusobacterium in tumor pathology. The findings of our investigation lay a foundation for further research into the roles of tumor microbe-derived metabolites in cancer.