An oral bacterial pyroptosis amplifier against malignant colon cancer

Abstract

The oncolytic microbe can trigger pyroptotic cancer cell death, but insufficient pyroptotic response of current microbe-based biotherapeutics restricts the antitumor efficiency. Herein, we report an oral bacterial pyroptosis amplifier composed of two bacterial strains, reductive Shewanella oneidensis MR-1 (abbreviated as MR-1) and engineered Escherichia coli (E. coli) with the overexpression of pyranose oxidase, augmenting the pyroptosis effect against colon and metastatic tumors. Each bacterium is camouflaged with hyaluronic acid to survive against the harsh gastrointestinal environment and to enrich in colon tumor sites. Upon the bacteria colonizing at the tumor site, iron sucrose is orally administrated. The following oral administration of Fe(Ⅲ)-contained iron sucrose leads to the intratumoral accumulation of Fe(Ⅱ) by the reduction characteristic of MR-1. Hydrogen peroxide (H2O2), synthesized by pyranose oxidase from E. coli, serves as the substrate for Fenton reaction to generate toxic hydroxyl radicals through Fe(Ⅱ)-H2O2-Fe(Ⅲ) recycling between both strains, thereby promoting immunogenic pyroptosis inside the tumor. This can potentiate lymphocyte activation in the gastrointestinal tissues, exerting significant therapeutic efficacy in multiple colon metastatic tumor models. This study offers promising insight into developing future microbe biotherapeutics with enhanced pyroptosis activity in cancer immunotherapy.