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@Delta St, has been constructed by conjugating PEGylated Cu2O nanoparticles on the surface of an engineered Salmonella typhimurium strain (Delta St). Owing to the natural hypoxia tropism of Delta St, Cu2O@Delta St could selectively colonize hypoxic solid tumors, thus minimizing the adverse effects of the bacteria on normal tissues. Upon bacterial metabolism within the tumor, Cu2O@Delta St 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 (CuO)-O-2 into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decomposing endogenous H2O2 into cytotoxic hydroxyl radicals (center dot 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.

Automated summary

A bacterial metabolism-initiated and photothermal-enhanced nanocatalytic therapy strategy has been developed to completely eradicate tumors and induce immunological memory effect.