Enhanced Immunogenic Cell Death and Antigen Presentation <i>via</i> Engineered <i>Bifidobacterium bifidum</i> to Boost Chemo-immunotherapy.

Abstract

The immunogenic cell death (ICD) of tumor cells has aroused great interest in the field of immunotherapy, mainly due to the production of plentiful tumor-associated antigens (TAAs) and damage-associated molecule patterns. However, doxorubicin (DOX)-induced tumor-specific T-cell-mediated immune response is usually very weak because of antigen presentation deficiency and the immunosuppressive tumor microenvironment (ITME). Herein, the probiotic <i>Bifidobacterium bifidum</i> (Bi) was covalently modified with DOX-loaded CaP/SiO₂ nanoparticles (DNPs@Bi) for tumor therapy. On one hand, the pH-responsive release of DOX could induce chemotherapy and ICD in the ITME. On the other hand, tumor-targeting Bi is able to significantly enhance the presentation of TAAs from B16F10 cells to DCs <i>via</i> Cx43-dependent gap junctions. Due to the combination of enhanced ICD and TAAs presentation, the maturation of DCs and the infiltration of cytotoxic T lymphocytes in the ITME were stimulated. As a result, <i>in vivo</i> antitumor experiments demonstrated that DNPs@Bi prolonged the survival rate and significantly inhibited the tumor progression and metastasis. This strategy of bacterial-driven hypoxia-targeting delivery systems offers a promising approach to tumor chemo-immunotherapy.