Fusobacterium nucleatum
is a critical microbe that contributes to colorectal cancer progression and chemoresistance. However, whether and how
F. nucleatum
regulates colorectal cancer stem‐like cells (CCSCs) remains unknown. Here, the authors show that
F. nucleatum
promotes CCSC self‐renewal, and non‐CCSCs to acquire CCSC features by manipulating cellular lipid accumulation.
F. nucleatum
infection decreases lipid accumulation in CCSCs by enhancing fatty acid oxidation, thus promoting CCSC self‐renewal. In contrast,
F. nucleatum
increases lipid accumulation in non‐CCSCs by promoting fatty acid formation. Lipids are deposited as lipid droplets, which recruits Numb, a key cell fate regulator, through the AP2A/ACSL3 complex, and MDM2, an E3 ubiquitin ligase, though VCP and UBXD8. On lipid droplets, Numb is degraded by MDM2, activating Notch signaling, thus promoting gain of stem‐like cell features. Their findings demonstrate that
F. nucleatum
directly manipulates colorectal cancer cell fate and reveal the mechanism of lipid droplet‐mediated Numb degradation for activating Notch signaling.