Oral oncolytic magnetotactic bacteria elicit anti-colorectal tumor immunity and reprogram microbiota metabolism

Therapeutic outcomes of colorectal cancer (CRC) are influenced by intestinal microbiota and metabolites. To leverage the tumor-tropism and microbiota-regulating properties of bacteria, we developed oncolytic magnetotactic bacteria (MSR-CPT/APPs) loaded with camptothecin (CPT) and anti-PD-L1 peptide (APP) for targeted chemo-magnetothermal immunotherapy of CRC. To further achieve oral delivery, MSR-CPT/APPs were coated with mulberry leaf lipids and Pluronic F127 (LPs). When exposed to an alternating magnetic field, MSR-CPT/APP@LPs penetrated colonic mucus and reached deep-seated tumors. They elevated proinflammatory cytokine secretion, prolonged T cell recruitment, and reduced immunosuppressive cell proportions by activating the cGAS-STING pathway, inducing immunogenic cell death, and facilitating macrophage polarization to M1 phenotype. Oral MSR-CPT/APP@LPs increased the relative abundances of crucial commensal microorganisms (<i>e.g</i>., <i>Lachnospiraceae</i> family and <i>Alistipes</i>) and influenced their metabolites, like elevating beneficial metabolites (short-chain fatty acids and citrulline) levels and decreasing harmful metabolites (l-glutamine and kynurenic acid) amounts, thereby remodeling the tumor immune microenvironment. Overall, MSR-CPT/APP@LPs foster a supportive intestinal environment and mitigate immunosuppression, achieving the eradication of both primary and distant colorectal tumors.