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Abstract: Colorectal cancer (CRC) remains among the most prevalent and deadliest malignancies worldwide, with limited survival outcomes, particularly in patients with metastatic disease. Despite advances in immunotherapy, immune checkpoint inhibitors (ICIs) have shown efficacy mainly in mismatch repair-deficient (dMMR) CRC, while responses in mismatch repair-proficient (pMMR) microsatellite-stable (MSS) cases remain limited. Emerging evidence highlights the gut microbiome as a critical factor influencing CRC development, progression, and therapeutic response. In particular, the gut microbiota has been shown to affect the efficacy of ICIs, with dysbiosis contributing to treatment resistance and specific microbial taxa enhancing antitumor immune responses. Preclinical and clinical studies have demonstrated that microbiome-based interventions, including probiotics, fecal microbiota transplantation (FMT), dietary modulation, and traditional medicines, can restore immune function by modulating immune cell populations and producing immunoregulatory metabolites. These effects may enhance responsiveness to ICIs and contribute to the suppression of tumor growth. However, we also address key limitations in this field, including inconsistent findings and safety concerns, such as infection risks, to guide future translational efforts. Overall, while microbiome-based interventions represent a promising adjunct to CRC immunotherapy, rigorous clinical trials and mechanistic validation are required before their routine clinical implementation.