分子识别驱动的细胞器交联诱导内质网应激和线粒体功能障碍以增强癌症免疫治疗。

IF 16.9
Mian Tang, Junteng Qiu, Yunfeng Lu, Zhongke Liu, Yin Liu, Chenhui Luo, Chunhai Fan, Ruibing Wang
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引用次数: 0

摘要

细胞器通过高度专业化的分工、动态的相互作用以及广泛的胞间信息交换来维持细胞内稳态,从而保证生物体的生理功能。虽然针对特定细胞器调节或破坏其功能的功能化聚合物已被开发用于治疗应用,但能够操纵两种或两种以上类型的关键细胞器的大分子系统仍然很少。在此,我们设计了环糊精和金刚烷衍生物,分别靶向内质网和线粒体,通过特定的分子识别方法在亚细胞细胞器水平上实现对这两种细胞器的精确空间操纵。这种方法选择性地诱导内质网和线粒体之间的异常连接,破坏它们的功能协同,引发多种细胞应激反应,如Ca2+稳态失衡、活性氧(ROS)爆发、能量代谢紊乱,最终导致严重的免疫原性细胞死亡(ICD)。通过将“冷”肿瘤转化为“热”肿瘤,该策略为肿瘤免疫治疗提供了超分子视角。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular Recognition Driven Organelle Cross-Linking Induces Endoplasmic Reticulum Stress and Mitochondrial Dysfunction to Potentiate Cancer Immunotherapy.

Organelles maintain cellular homeostasis through highly specialized division of labor, dynamic interactions, as well as extensive inter-organellar information exchange, thereby ensuring the physiological functions of organisms. Although functionalized polymers that target a specific organelle to modulate or disrupt their function have been developed for therapeutic applications, macromolecular systems capable of manipulating two or more types of key organelles remain rare. Here, we designed cyclodextrin and adamantane derivatives that can respectively target endoplasmic reticulum (ER) and mitochondria, to achieve precise spatial manipulation of both organelles at the subcellular organelle level via a specific molecular recognition approach. This approach selectively induced unusual junctions between the ER and mitochondria, disrupting their functional synergy, triggering multiple cellular stress responses, such as Ca2+ homeostasis imbalance, reactive oxygen species (ROS) burst, energy metabolism disorder, and ultimately leading to severe immunogenic cell death (ICD). By converting "cold" tumors into "hot" tumors, this strategy provides a supramolecular perspective for tumor immunotherapy.

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