The efficacy of
cancer therapies is significantly compromised by the immunosuppressive
tumor milieu. Herein, we introduce a previously unidentified therapeutic strategy that harnesses the synergistic potential of
chitosan-coated bacterial vesicles and a targeted chemotherapeutic agent to activate dendritic cells, thereby reshaping the immunosuppressive milieu for enhanced
cancer therapy. Our study focuses on the
protein-mediated modification of bacterium-derived minicells with
chitosan molecules, facilitating the precise delivery of
Doxorubicin to
tumor sites guided by
folate-mediated homing cues. These engineered minicells demonstrate remarkable specificity in targeting lung
carcinomas, triggering immunogenic cell death and releasing
tumor antigens and damage-associated molecular patterns, including
calreticulin and high mobility group box 1. Additionally, the
chitosan coating, coupled with
bacterial DNA from the minicells, initiates the generation of
reactive oxygen species and
mitochondrial DNA release. These orchestrated events culminate in dendritic cell maturation via activation of the stimulator of
interferon genes signaling pathway, resulting in the recruitment of CD4+ and CD8+ cytotoxic T cells and the secretion of
interferon-β,
interferon-γ, and
interleukin-12. Consequently, this integrated approach disrupts the immunosuppressive tumor microenvironment, impeding
tumor progression. By leveraging bacterial vesicles as potent dendritic cell activators, our strategy presents a promising paradigm for synergistic
cancer treatment, seamlessly integrating
chemotherapy and
immunotherapy.