Inflammation‐Driven Doxycycline‐Glucose Oxidase Nanoparticle Induce Starvation‐/Chemodynamic‐/Immunotherapy against Intratumoral Bacteria‐Assisted Tumor Development

Abstract Seeking novel epitopes of tumors has become the major task of immunotherapy in recent years. Evidence has revealed the presence of diverse bacterium in various tumors, which are reported to promote tumor development by upregulating cyclooxygenase II for inflammation induction and assisting tumor metastasis. It has been confirmed that T cell immunity elicited by bacteria can cross‐react with MHC‐I‐restricted antigens present in cancer cells, indicating the T cells responding to microbes may also contribute to antitumor immune responses. These findings enlighten the authors to consider intratumoral bacteria as a novel source of immune epitopes, and antibiotics are therefore emerging as necessary therapeutic agents. However, the unexpected biodistribution of antibiotics results in imbalance in other microbial communities in the body. To overcome this challenge and increase drug loading efficiency, a biomimetic self‐assembly metal‐phenolic nanoparticle (DGMNP@CM NPs) is constructed by combining Fe 3+ , doxycycline (Doxy), glucose oxidase (GOx), and wrapped by inflammation‐driven macrophage membrane. The inflammation‐guided macrophage membrane enables the NPs active tumor targeting ability. The metal‐phenolic structure lyses at acidic tumor microenvironment to release Doxy and GOx. The broad‐spectrum antibiotic Doxy enters cytoplasm to kill tumor‐resident bacteria, leading to the reduction of bacteria‐promoted tumor metastasis. The exciting results are observed in different tumor cell lines and corresponding bacterial strains. Fe 3+ and GOx synergistically induce the Fenton reaction in tumor tissues under oxidative stress, triggering chemodynamic therapy to eliminate all tumor cells and microbes. The exposed internal antigens then recruit and activate specific antitumor responses, especially the cross‐reaction of T cell immunity. Numerous cytokines are released in tumors and thus amplify systemic immune responses. A synergistic antitumor effect is achieved using DGMNP@CM NPs by dual target of both intratumoral bacteria and tumor cells. The authors hope this research can promote more studies on the new epitopes from tumor‐resident microbes and offering a novel insight for clinical immunotherapy practices.