Gut microbiota and the colorectal cancer tumor microenvironment: From carcinogenic mechanisms to therapeutic opportunities

Colorectal cancer (CRC) is ranked as the third most common tumor globally, representing approximately 10% of all cancer cases, and is the second primary cause of cancer-associated mortality. Existing therapeutic approaches demonstrate limited efficacy against CRC, partially due to the immunosuppressive tumor microenvironment (TME). In recent years, substantial evidence indicates that dysbiosis of the gut microbiota and its metabolic products is closely associated with the initiation, progression, and prognostic outcomes of CRC. In this minireview, we systematically elaborate on how these microbes and their metabolites directly impair intestinal epithelial integrity, activate cancer-associated fibroblasts, remodel tumor vasculature, and critically, sculpt an immunosuppressive landscape by modulating T cells, dendritic cells, and tumor-associated macrophages. We highlight the translational potential of targeting the gut microbiota, including fecal microbiota transplantation, probiotics, and engineered microbial systems, to reprogram the TME and overcome resistance to immunotherapy and chemotherapy. A deeper understanding of the microbiota-TME axis is essential for developing novel diagnostic and therapeutic paradigms for CRC.