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.

中文翻译：

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工程细菌操纵半胱氨酸代谢以促进基于铁死亡的胰腺导管腺癌治疗


半胱氨酸代谢是胰腺导管腺癌 （PDAC） 防御铁死亡的关键决定因素。阻断半胱氨酸代谢可能通过在肿瘤代谢过程中产生脂质过氧化物来触发 PDAC 细胞中有效的铁死亡。然而，目前限制半胱氨酸可用性的方法不足，由于肿瘤靶向和补偿半胱氨酸来源不足，无法有效阻断半胱氨酸代谢。受硫代谢细菌的启发，使用合成生物学开发一种能够直接消耗半胱氨酸以阻止其新陈代谢的工程细菌。作为一种活的药物，这些工程细菌在肿瘤缺氧的刺激下定植于肿瘤并不断产生工程化的囊肿 （e） 酶 （CGL）。CGL 耗尽底物半胱氨酸，完全阻碍半胱氨酸代谢。这个过程瓦解了 PDAC 细胞中的铁死亡防御系统，触发了有效的铁死亡，并实现了有效的治疗。结果表明，设计用于半胱氨酸代谢调节的工程细菌在阻断半胱氨酸代谢的功效、持久性和精确性方面具有无与伦比的优势，使其非常适合 PDAC 的铁死亡治疗。