Engineered Microbial Nanohybrids for Tumor‐Mediated NIR II Photothermal Enhanced Ferroptosis/Cuproptosis and Immunotherapy

Abstract The colon tumor microenvironment has a high concentration of H 2 S and glutathione, which is highly immunosuppressive and adverse to multiple therapeutic methodologies such as ferroptosis. Here, an engineered microbial nanohybrid based on Escherichia coli ( E. coli ) and Cu 2 O nanoparticles to specific colon tumor therapy and immunosuppression reversion is reported. The as‐prepared E. coli @Cu 2 O hybrid can accumulate in tumor sites upon intravenous injection, and Cu 2 O nanoparticles convert to Cu x S by consuming the endogenous H 2 S, which exhibits strong photothermal conversion at near‐infrared II (NIR II) biological window. Furthermore, E. coli @Cu 2 O is able to induce cellular ferroptosis and cuproptosis through inactivation of glutathione peroxidase 4 and aggregation of dihydrolipoamide S‐acetyltransferase, respectively. Photothermal‐enhanced ferroptosis/cuproptosis achieved by E. coli @Cu 2 O reverses the immunosuppression of colon tumors by triggering dendritic cell maturation (about 30%) and T cell activation (about 50% CD8 + T cells). Concerted with immune checkpoint blockade, the engineered microbial nanohybrid can inhibit the growth of abscopal tumors upon NIR illumination. Overall, the designed microbial nanohybrid can achieve tumor‐specific photothermal‐enhanced ferroptosis/cuproptosis and immunosuppression reversion, showing promise in precise tumor therapy in future clinical translation.