Targeted depletion of intratumoral bacteria using PEGylated metronidazole to augment cancer treatment efficacy.

Abstract

Since the infiltration of intratumoral microbiota is associated with aggressive phenotypes of cancer, eliminating bacteria within tumors has become an attractive approach to cancer treatment. By self-assembly of PEGylated metronidazole (MTI-PEG), we developed a nanosized antibiotic that effectively eliminates intratumoral bacteria without causing gut microbiome dysbiosis. In Fusobacterium nucleatum spp (Fn) colonized tumor models, we observed significant adjuvant effects of MTI-PEG on chemotherapy, immunotherapy and targeted therapy through reversing drug resistance through the modulation of autophagy, the human T-cell immunoglobulin and ITIM domain (TIGIT) and the phosphatidylinositol-3-kinase/protein kinase B (PI3K-AKT) signaling pathway, respectively, while reshaping immune landscape of tumor microenvironment. The encouraging results indicate a promising future for MTI-PEG in microbiome-infiltrated tumors, with potential to improve the overall therapeutic efficacy of current cancer treatments.