Candida albicans synergizes with Fusobacterium nucleatum in colorectal cancer progression via the Flo9-RadD interaction.

Fusobacterium nucleatum tumor infiltration is a hallmark of colorectal cancer (CRC) progression. However, whether and how other microbes influence F. nucleatum in CRC remains unclear. Here, we discover that the commensal fungus Candida albicans synergizes with F. nucleatum to promote CRC pathogenesis and contributes to poor patient outcomes. Co-inoculation of C. albicans and F. nucleatum accelerates CRC progression compared to either microbe alone in animal models. C. albicans strains isolated from CRC patients exhibiting enhanced hyphal morphogenesis and elevated FLO9 expression promote F. nucleatum-mediated tumor growth. Mechanistically, through the Flo9-RadD interaction, C. albicans facilitates F. nucleatum localization to the colonic mucosa and promotes F. nucleatum-driven malignant transformation. Translationally, we demonstrate that L-arginine disrupts the interaction between C. albicans and F. nucleatum, reducing their synergistic pro-tumor activity in CRC models in vivo. These findings highlight fungal-bacterial interaction as a critical etiologic mechanism in CRC and a potential therapeutic target.