Microbiome and Treatment Resistance in Colorectal Cancer: Mechanisms and Solutions

Abstract

This review investigates the complex role of the gut microbiome in modulating treatment resistance in colorectal cancer (CRC), examining mechanisms that influence therapeutic outcomes across chemotherapy, immunotherapy, and targeted therapies. Through a systematic search of databases, including PubMed, Scopus, Embase, Web of Science, SciELO, and gray literature from Google Scholar, we identified relevant studies addressing microbial interactions with cancer treatments. Key insights reveal how specific microbial species, such as Fusobacterium nucleatum, impact chemotherapy efficacy by altering drug metabolism and promoting immune evasion. Genetic mutations in patients, notably in immune-regulatory genes like MSH2 and MLH1, further shape microbiome composition, contributing to an immunosuppressive environment that fosters CRC progression and resistance. The review also addresses immunotherapeutic outcomes, highlighting the role of microbial species in modulating immune checkpoints, such as PD-1 and PD-L1, and influencing CAR-T cell therapy. Microbial metabolites, including short-chain fatty acids, impact tumor microenvironment signaling pathways associated with resistance. Therapeutic strategies, such as dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation, are discussed as potential approaches to modify the microbiome, enhance treatment responses, and reduce recurrence risks. This synthesis underscores the need to explore further microbiome-targeted therapies and their integration into precision oncology for optimized CRC management.