Targeting Microbiome Metabolites: Reshaping Immunotherapy and Clinical Management Strategies for Colorectal Cancer

ABSTRACT The pathogenesis of colorectal cancer (CRC) is closely associated with gut microbial metabolites, which exert crucial regulatory effects within the tumor immune microenvironment. These metabolites play a dual role in CRC immunity: certain metabolites promote tumor progression by inducing chronic inflammation, recruiting myeloid‐derived suppressor cells, and suppressing CD8 + T cell function; while others, such as short‐chain fatty acids and tryptophan metabolites, enhance anti‐tumor immunity and improve the efficacy of immune checkpoint inhibitors (ICBs). This paper systematically explores intervention strategies targeting this mechanism, including probiotics, prebiotics, metabolite adjuvants, and their combination with immunotherapy to overcome ICB resistance. Furthermore, the analysis of specific metabolites (e.g., cholic acid derivatives) and microbial signatures (e.g., enrichment of F. nucleatum ) has been identified as a potential avenue for the development of novel non‐invasive biomarkers, which could facilitate early screening and differential diagnosis. Notwithstanding the challenges encountered in the clinical translation of these technologies, the integration of multi‐omics and artificial intelligence with the immunoregulatory mechanisms and diagnostic potential of metabolites holds great promise for advancing precision medicine in the comprehensive management of CRC.