Metabolic Regulation of Tumor Microenvironment with Biohybrid Bacterial Bioreactor for Enhanced Cancer Chemo‐Immunotherapy

Abstract Immunogenic cell death (ICD) induced by specific chemotherapeutic agents is often hampered by the immunosuppressive tumor microenvironment (TME). Here, a bacterial bioreactor E@Fe‐DOX, is developed, to enhance ICD‐mediated antitumor immunity by in situ manipulation of tumor metabolism‐immune interactions. The E@Fe‐DOX bioreactor is constructed by depositing doxorubicin‐loaded iron‐polyphenol nanoparticles on Eubacterium hallii, which can specifically target hypoxic tumor regions and release doxorubicin and Fe³⁺ to induce ICD. In addition, Eubacterium hallii can continuously convert intratumoral lactate to butyrate, which inhibits the polarization of pro‐tumoral M2‐like macrophages and improves the function of tumor‐infiltrating cytotoxic T cells. Furthermore, E@Fe‐DOX promotes the formation of immune cell‐aggregated tertiary lymph structures (TLS) to augment ICD‐induced antitumor immunity. In murine tumor models, E@Fe‐DOX significantly inhibits tumor growth and enhances immune checkpoint blockade (ICB) therapy. Overall, the developed living biomaterial offers a promising strategy to potentiate cancer chemo‐immunotherapy by continuously regulating the intratumoral immuno‐metabolic microenvironment.