Unlocking Intratumoral Bacteria-suppressed Ferroptosis with Two-in-One Nanoassemblies for Enhanced Colorectal Cancer Treatment

Intratumoral bacteria are reported to have a critical influence on cancer progression and treatment. Here, we show that Fusobacterium nucleatum (F. nucleatum) inhibits the antitumor efficacy of multiple drugs against colorectal cancer (CRC), particularly sorafenib. We further demonstrate that F. nucleatum aggravates hypoxia level in CRC patients, resulting in the suppression of ferroptosis through upregulation of System XC-. Based on this discovery, we develop two-in-one nanoaseemblies composed of artemether-metronidazole conjugate (ART-MET, AM) and sorafenib for eliminating intratumoral bacteria and enhancing ferroptosis. Interestingly, AM exhibits dual antibacterial and antitumor activity, effectively killing intratumoral bacteria while synergizing with sorafenib to amplify tumor ferroptosis through NADPH depletion and ROS generation. Consequently, the nanoassemblies significantly inhibit tumor growth and metastasis by unlocking intratumoral bacteria-mediated ferroptosis resistance, with remarkable synergistic antitumor effects in patient-derived organoid, orthotopic, and ectopic CRC model. Our study not only explores the mechanism of sorafenib resistance to CRC but also represents a promising clinical treatment strategy for CRC.