Qiao Chaoqiang, Wang Lexuan, Huang Chuting, Jia Qian, Bao Weier, Guo Peilin, Tan Dengxu, Chen Zhuang, Shi Changhong, Rao Zhiping, Zhang Ruili, Wei Wei, Wang Zhongliang
Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, P. R. China.
Guangzhou Institute of Technology, Xidian University, Guangzhou, 510555, P. R. China.
Adv Mater. 2025 Feb;37(6):e2412982. doi: 10.1002/adma.202412982. Epub 2024 Dec 18.
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.
半胱氨酸代谢是胰腺导管腺癌（PDAC）抵御铁死亡的关键决定因素。阻断半胱氨酸代谢可能会在肿瘤代谢过程中通过产生脂质过氧化物触发PDAC细胞中强烈的铁死亡。然而，目前限制半胱氨酸可用性的方法存在不足，由于肿瘤靶向性不足和半胱氨酸补偿来源，无法有效阻断半胱氨酸代谢。受硫代谢细菌的启发，利用合成生物学开发一种能够直接消耗半胱氨酸以阻断其代谢的工程菌。作为一种活体药物，这些工程菌在肿瘤中定殖，并在肿瘤缺氧的刺激下持续产生工程化的半胱氨酸酶（CGL）。CGL耗尽底物半胱氨酸，完全阻碍半胱氨酸代谢。这一过程瓦解了PDAC细胞中的铁死亡防御系统，触发强烈的铁死亡，并实现有效治疗。结果表明，设计用于调节半胱氨酸代谢的工程菌在阻断半胱氨酸代谢的疗效、持久性和精准性方面具有无与伦比的优势，使其非常适合对PDAC进行有效的铁死亡治疗。
