Folate Metabolism in Colorectal Cancer Reveals Links Between Clinical and Immune Traits, Identifying CYP26A1 as a Target

Background: Folic acid plays a key role in cellular regulation and metabolism, commonly found in dietary supplements. However, its complex role in colorectal cancer (CRC), particularly in metabolism and immune evasion, remains unclear. Methods: We developed the FMRG_score system using machine learning algorithms based on TCGA and GEO databases to assess modification patterns influencing CRC patients' clinical and immune characteristics. The system’s reliability was validated using multiple external clinical cohorts receiving immunotherapy. We further explored the relationships between FMRGs-related features and clinical traits, mutation profiles, biological functions, immune infiltration, therapy response, and drug sensitivity. Results: By combining in vitro experiments and bioinformatics analysis, we established a 9-gene risk model associated with folate metabolism to predict CRC prognosis. Notably, CYP26A1, a key component of the model, was upregulated in CRC tissues, promoting cell proliferation, migration, and invasion. Significant differences in clinical traits, immune cell infiltration, immune checkpoint expression, therapy response, and drug sensitivity were observed between risk groups. Conclusion: The folate scoring system can assess CRC prognosis, tumor microenvironment, and immune therapy response. This is the first study proposing CYP26A1 as an oncogene in CRC.