Engineered Bacteria Manipulate Cysteine Metabolism to Boost Ferroptosis‐Based Pancreatic Ductal Adenocarcinoma Therapy

Abstract Cysteine metabolism is a key determinant of the defense against ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Blocking cysteine metabolism may trigger potent ferroptosis in PDAC cells by generating lipid peroxides during tumor metabolic processes. However, current methods to limit cysteine availability fall short, failing to efficiently block cysteine metabolism due to inadequate tumor targeting and compensatory cysteine sources. Inspired by sulfur‐metabolizing bacteria, synthetic biology to develop an engineered bacterium capable of directly depleting cysteine to block its metabolism is used. Acting as a living drug, these engineered bacteria colonize the tumor and continuously produce engineered cyst(e)inase enzyme (CGL) under the stimulation of tumor hypoxia. The CGL exhausts the substrate cysteine, completely impeding cysteine metabolism. This process dismantles the ferroptosis defense system in PDAC cells, triggers potent ferroptosis, and achieves efficient treatment. The results demonstrate that engineered bacteria designed for cysteine metabolism modulation possess unparalleled advantages in efficacy, persistence, and precision in blocking cysteine metabolism, making them highly suitable for effective ferroptosis treatment of PDAC.