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 Cu(2)O@ΔSt, has been constructed by conjugating PEGylated Cu(2)O nanoparticles on the surface of an engineered Salmonella typhimurium strain (ΔSt). Owing to the natural hypoxia tropism of ΔSt, Cu(2)O@ΔSt could selectively colonize hypoxic solid tumors, thus minimizing the adverse effects of the bacteria on normal tissues. Upon bacterial metabolism within the tumor, Cu(2)O@ΔSt generates H(2)S gas and other acidic substances in the tumor microenvironment (TME), which will in situ trigger the sulfidation of Cu(2)O to form CuS facilitating tumor-specific photothermal therapy (PTT) under local NIR laser irradiation on the one hand. Meanwhile, the dissolved Cu(+) ions from Cu(2)O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decomposing endogenous H(2)O(2) into 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. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40820-022-00951-0.