Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy

The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy.Herein,we report a bacterial metabolism-initiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses.Briefly,a microbiotic nanomedicine,designated as Cu2O@ΔSt,has been constructed by conjugating PEGylated Cu2O nanoparticles on the surface of an engineered Salmonella typhimurium strain(ΔSt).Owing to the natural hypoxia tropism of ΔSt,Cu2O@ΔSt could selectively colonize hypoxic solid tumors,thus minimizing the adverse effects of the bacteria on normal tissues.Upon bacterial metabolism within the tumor,Cu2O@ΔSt generates H2S gas and other acidic substances in the tumor microenvironment(TME),which will in situ trigger the sulfidation of Cu2O to form CuS facilitating tumor-specific photothermal therapy(PTT) under local NIR laser irradiation on the one hand.Meanwhile,the dissolved Cu+ions from Cu2O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decomposing endogenous H2O2into cytotoxic hydroxyl radicals(·OH) on the other hand.Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns,thereby sensitizing tumors to checkpoint blockade(ICB) therapy.The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors,and more importantly,induces a powerful immunological memory effect after the primary tumor ablation.