Dietary Riboflavin Supplementation Suppresses Colorectal Cancer Progression by Restoring the Function Effector of CD8+ T Cells

Tumor cells have a competitive edge in nutrient uptake, leading to immune cell nutrient deprivation within the tumor microenvironment (TME) and suppressing anti-tumor immunity. However, the key nutrient deprived by intestinal tumor cells and effective intervention strategies remains unidentified. Using organoid models and metabolomics, we clarified riboflavin as the most preferential nutrient for intestinal tumor cells over normal epithelial cells. After confirming in vitro that riboflavin supplementation did not promote tumor cell proliferation, we found in vivo that drinking water with riboflavin effectively inhibited murine colorectal tumor growth with enhanced intra-tumoral CD8⁺ T-cell cytotoxicity. We further demonstrated the indispensable role of adequate riboflavin in maintaining effector CD8⁺ T cells and revealed intestinal tumor cells overexpressed the riboflavin transporter SLC52A2, depleting riboflavin from CD8⁺ T cells and dampening their cytotoxicity, which can be restored by riboflavin supplementation. Our work clarified the critical nutrient and immune evasion mechanism, suggesting riboflavin supplementation as potential therapy to enhance anti-tumor immunity in colorectal cancer.