Gut microbiome-shaped chemotherapy responses across cancer types: mechanisms of resistance, biomarkers, and targeted interventions

Abstract

Cytotoxic chemotherapy remains an important component of multimodal treatment for many solid tumors, but resistance and dose-limiting toxicities continue to constrain clinical benefit. The gut microbiome can influence chemotherapy response through microbial drug biotransformation, metabolite signaling, intestinal-barrier integrity, systemic immune regulation, and tumor-cell stress and death pathways. Across solid tumors, the evidence is strongest in colorectal cancer, where clinical associations are supported by increasingly detailed mechanistic and interventional studies; evidence in many extraintestinal cancers remains less mature and is dominated by smaller observational cohorts and selected preclinical models. Importantly, gut-derived systemic effects should be distinguished from local or tumor-associated microbial mechanisms, and direct tumor-cell resistance should be separated from altered drug exposure and toxicity-mediated reductions in relative dose intensity. Microbiota-associated and metabolic biomarkers and microbiota-targeted interventions show potential for treatment stratification, toxicity prediction, and therapeutic modulation, but clinical translation remains limited by heterogeneous cohorts, incomplete causal validation, variable engraftment and strain specificity, and safety and standardization requirements. Overall, the microbiome is best viewed as a cancer- and regimen-specific modifier of chemotherapy rather than a universal determinant of response. Prospective, mechanism-matched studies are needed to establish whether microbiome-guided strategies can improve treatment efficacy, tolerance, and completion.