Synthetically engineered probiotic suppresses colorectal cancer via inhibition of Wnt/β-catenin signaling.

Abstract

Colorectal cancer (CRC) is one of the most prevalent malignancies globally. Recent breakthrough of synthetic biology stimulates the utilization of engineered bacteria for cancer diagnosis and treatment. We perform a comprehensive fecal metabolomic analysis in CRC mouse models and patients and identify ornithine as a specific metabolic biomarker for tumor development. We subsequently engineer an E. coli Nissle 1917 (EcN)-based bioluminescent reporter via ornithine-responsive tumor detection. For therapeutic intervention, we construct a probiotic system that locally releases Dickkopf 3 (DKK3), a potent Wnt signaling antagonist to retard tumor growth. Oral administration of the bacteria demonstrates reduced tumor burden and improved survival outcomes in multiple preclinical models, and the anticancer efficacy is further confirmed in CRC patient-derived organoids and patient-derived xenograft (PDX) model. Taken together, we develop a novel probiotic platform combing non-invasive diagnostic capability with targeted therapeutic delivery for CRC management, underscoring the strong potential for clinical translation and eventual application in preventive oncology.