Nanodrug engineered bacteria for tumor-targeted and synergistic photothermal immunotherapy

Cancer immunotherapy is an attractive strategy clinically, in which small molecule immune checkpoint inhibitors (ICIs) are widely used due to their low cost, short half-life, and high diffusion rate in tumor after oral administration. However, this monotherapy is accompanied by limited efficacy and undesirable systemic side effects. Herein, we proposed a simple and safe strategy to engineer bacteria for tumor-targeted and synergistic therapy. First, the photothermal nanoagent polydopamine (PDA) was coated on the surface of non-pathogenic Escherichia coli MG1655 through in situ polymerization, followed by the noncovalent attachment of an indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor NLG919 to result in MG1655@PDA-NLG. The functionalized bacteria exhibited outstanding photothermal conversion properties with unaffected viability and bioactivity. In a murine subcutaneous CT26 colon tumor model, they effectively accumulated in the tumor within 12 h post intravenous injection and were completely cleared from the major organs by 72 h with negligible hematological toxicity, confirming the excellent hypoxic tumor-targeting ability and biosafety. Under near-infrared light irradiation, the engineered bacteria significantly inhibited tumor growth by over 90% on the basis of photothermal effect and induced immunogenic cell death (ICD) to promote dendritic cell (DC) maturation, which synergized with immunosuppression of tryptophan (Trp) metabolism for enhanced CD4+ and CD8+ T cell infiltration. This work would inspire the development of multifunctional bacteria through surface integration with multiple therapeutic agents for precise and combined cancer immunotherapy.