Virome and colorectal cancer: Paving the way for future explorations and clinical applications

The pathogenesis of colorectal cancer (CRC) is inextricably linked to the gut microbiome. However, research has historically concentrated on the bacteriome, leaving the gut virome (predominantly composed of bacteriophages) largely unexplored as biological “dark matter”. Recent advancements have illuminated the dual regulatory role of phages within the tumor microenvironment (TME), where they intricately modulate both bacterial community dynamics and host immune responses. This review synthesizes current evidence on viral dysbiosis throughout CRC progression and evaluates the translational potential of virome signatures as highly specific, non-invasive diagnostic and prognostic biomarkers. We then explore emerging virome-based interventions, including precision phage therapies, aimed at reshaping the TME and enhancing synergistic responses to conventional treatments and immunotherapy. To propel the field from correlative observations to actionable clinical applications, significant translational hurdles must be overcome. We highlight the urgent need for standardized bioinformatics pipelines to address reproducibility challenges and emphasize the utility of advanced, culture-independent methodologies like single-cell viral tagging to accurately map host-phage interaction networks. Finally, we advocate for the integration of large-animal models, such as CRC pig models, to validate the causal roles and longitudinal dynamics of the virome, ultimately bridging the gap between basic exploration and precision gastrointestinal oncology.