Therapeutic Targeting of the Cancer Microbiome and Metabolome: Ongoing Trials and Future Directions for the Surgical Oncologist

The role of the human microbiome in cancer development, progression, and response to therapy has moved from correlative curiosity to demonstrated impact on tumor biology. This represents a critical factor for surgical oncologists as they not only resect these tumors, but also direct perioperative antimicrobial exposure and increasingly co-manage neoadjuvant and surveillance pathways in which microbial state may predict and modify response. This review summarizes the basis for therapeutic modulation of the cancer microbiome and metabolome in a contemporary clinical-trial landscape across four broad strategies: additive (fecal microbiota transplantation, defined consortia, and live biotherapeutic products), subtractive (targeted antimicrobials), dietary and metabolome-directed interventions, and engineered or next-generation platforms. Particular attention is given to subtractive approaches in colon and rectal cancer and to the underexplored perioperative interface between the microbiome and surgical outcomes such as anastomotic leak. We outline the principal methodological and translational obstacles, including low-biomass contamination, causal inference, unintended antibiotic effects, and product standardization. Looking ahead, we propose roles for surgeons across the care continuum, from biospecimen stewardship and trial referral to integration of microbiome and circulating tumor DNA signals in surveillance.