A bulldozer driven by anoxic bacteria for pancreatic cancer chemo-immunotherapy

Immune evasion is a major obstacle for pancreatic ductal adenocarcinoma (PDAC) therapy. Inhibition of autophagy can improve antigen presentation and enlarge immunogenic cell death (ICD) effect to generate a strong anti-tumor immune response. However, abundant extracellular matrix dominated by hyaluronic acid (HA) hinders the deep penetration of autophagy inhibitors and ICD inducers. Herein, an intelligent autophagy inhibitor hydroxychloroquine (HCQ) and chemotherapeutic drug doxorubicin (DOX) co-loaded bulldozer (HD@HH/EcN) driven by anoxic bacteria was constructed for PDAC chemo-immunotherapy. Results demonstrated that probiotic Escherichia coli 1917 (EcN) could carry hyaluronidases (HAases)-hybrided albumin nanoparticles (HD@HH) to reach PDAC tumor tissue quickly and accurately. Thereafter, HAases can efficiently cleave the tumor matrix barrier and promote HD@HH/EcN to accumulate at tumor hypoxic core significantly. After that, high level of glutathione (GSH) in tumor microenvironment (TME) induces intermolecular disulfide bond in HD@HH nanoparticles breakage, to precisely release HCQ and DOX. DOX can induce ICD effect. Meanwhile, HCQ can amplify DOX induced ICD effect by inhibiting tumor autophagy, which further increase cell surface expression of major histocompatibility complex class I (MHC-I) and augment recruitment of CD8+ T cell to improve immunosuppressive TME. This study provides a new strategy for PDAC chemo-immunotherapy.

Automated summary

Immune evasion is a challenge in PDAC therapy. Inhibiting autophagy improves antigen presentation and enhances immunogenic cell death (ICD) to stimulate anti-tumor immune response. However, the abundance of hyaluronic acid (HA)-dominated extracellular matrix hinders the penetration of autophagy inhibitors and ICD inducers. In this study, an intelligent system using hydroxychloroquine (HCQ) and doxorubicin (DOX) co-loaded into bacteria was developed for PDAC chemo-immunotherapy. The results showed that the system effectively targeted the tumor tissue, overcame the matrix barrier, and released HCQ and DOX in the tumor microenvironment to induce ICD and inhibit autophagy, thus improving the immunosuppressive TME and providing a new strategy for PDAC therapy.