Bacteria‐Mediated Targeted Delivery and Deep Tumor Penetration of a Pt(IV)‐Drug Enables Synergistic Chemo‐Immunotherapy

ABSTRACT Platinum‐based drugs are clinically vital for cancer treatment but suffer from off‐target cytotoxicity and poor tumor penetration. To overcome these limitations, we designed a tumor‐targeted Pt(IV) drug‐bacteria conjugate ( Pt‐EcN‐HER2 ). This conjugate exploits the inherent tumor tropism of probiotic bacterium Escherichia coli Nissle 1917 (EcN) to achieve targeted accumulation and deep penetration within the tumor microenvironment (TME). Once localized, elevated intratumoral hydrogen peroxide (H 2 O 2 ) and glutathione (GSH) activate the Pt(IV) drug. Activation simultaneously releases cytotoxic cisplatin and an adenosine A2A receptor (A2AR) antagonist within the TME. The released cisplatin induces DNA damage and cell death, amplified by co‐occurring depletion of reductants, promoting multiple death pathways. Concurrently, the A2AR antagonist competitively blocks adenosine‐mediated immunosuppressive signaling, activating immune cells in TME. This dual chemo‐immunotherapeutic action enables effective tumor eradication. The bacteria‐mediated delivery strategy fundamentally addresses penetration barriers, enhances tumor‐specific Pt(IV) drug delivery and activation, mitigates systemic toxicity, and overcomes TME immunosuppression, thereby significantly potentiating platinum‐based chemo‐immunotherapy for solid tumors.