The intricate interplay of microbial metabolomics and carcinogenesis: a spotlight on mechanistic pathways, clinical implications and methodological challenges

Cancer is increasingly recognized to involve profound metabolic reprogramming, where the resident human microbiome acts as a "second genome" that fundamentally influences health and disease. At the intersection of oncology and microbiology lies the microbial metabolome, a comprehensive set of small-molecule metabolites that serve as the primary functional effectors between the microbiome and the host. We synthesize mechanistic evidence across hematologic malignancies as well as solid tumors including colorectal, pancreatic, breast, liver, and head and neck cancers. Pro-carcinogenic metabolites, such as secondary bile acids and bacterial genotoxins like colibactin, drive malignancy through chronic inflammation, direct DNA damage, and oncogenic signaling. Conversely, protective metabolites, predominantly short-chain fatty acids like butyrate, counteract cancer progression through immune modulation, selective apoptosis, and epigenetic regulation. This review examines the microbial metabolome as a "double-edged sword" in carcinogenesis, detailing how these molecules can either promote or suppress tumorigenesis depending on their identity, concentration, and the host environment. The review further explores the translational potential of microbial metabolomics in clinical oncology. We highlight the emerging role of metabolites as diagnostic and prognostic biomarkers and their capacity to modulate the efficacy and toxicity of chemotherapy and immunotherapy. Finally, we address critical methodological hurdles, including the need for standardization and established causality while providing a roadmap for integrating metabolomic profiling into a new era of personalized precision oncology.