Biohybrid system EcN@PB for reshaping tumor immunosuppressive microenvironment to improve photothermal therapy induced antitumor immune response

Photothermal therapy (PTT) is a promising tumor treatment with high selectivity, precise targeting, and low side effects. It induces photothermal ablation of tumors, and activates anti-tumor immune response by promoting immunogenic cell death (ICD) of tumor cells. Prussian Blue (PB) mediated PTT has made great progress, but high interstitial fluid pressure and solid stress in tumors significantly inhibited PB accumulation and diffusion, seriously affecting its PTT effect. Herein, we constructed a novel biohybrid system EcN@PB to enhance the PB-mediated photothermal immunotherapy. EcN@PB utilized the inherent tumor targeting ability of EcN to achieve precise delivery of PB to the tumor. On tumor-bearing mouse model, we demonstrated that EcN@PB selectively accumulated in tumors and achieved efficient photothermal ablation upon near-infrared laser irradiation, effectively inhibited the growth of primary tumor. Moreover, EcN@PB-mediated PTT induced ICD in tumor cells, promoted the maturation of dendritic cells, enhanced the infiltration of cytotoxic T lymphocytes and inhibited the recruitment of regulatory T cells in tumor tissues. Notably, EcN, as an immune adjuvant, effectively induced the polarization of tumor-associated macrophages towards the anti-tumor M1 phenotype, further reshaped the tumor immune microenvironment and activated systemic anti-tumor immune response. Therefore, EcN@PB-mediated photothermal-immunotherapy significantly inhibited the growth of distant tumors and prevented recurrence. Overall, EcN@PB significantly enhanced the targeted delivery of PB to tumor tissues and offered a promising strategy for photothermal-immunotherapy by leveraging the pathogen-associated molecular patterns carried by EcN to activate anti-tumor immune response.