中国科学院化学研究所王春儒研究团队揭示了富勒烯醇劫持溶酶体破坏细胞器间的串扰，阻断由mTOR抑制剂预先激活的自噬，从而导致癌细胞PANoptosis。该项研究成果发表在2025年2月25日出版的《科学通报》上。

溶酶体、内质网和线粒体之间的亚细胞胞间串扰对癌细胞的生存至关重要，是癌症治疗的一个有希望的靶点；然而，有效地破坏这些互动网络是一项挑战。

本文提出了一种通信拦截策略，该策略通过溶酶体内容物泄漏及其轨迹破坏细胞器间串扰，并预先激活自噬通量，以增加溶酶体相关的自噬阻断，以防止这种亚细胞疾病的自我修复。简而言之，含有多个羟基（MF）的富勒烯醇通过直接相互作用撕裂溶酶体磷脂膜，使溶酶体内容物（钙离子和组织蛋白酶）渗漏到细胞质中，从而导致内质网应激和线粒体功能障碍，导致氧化还原失衡和代谢重编程。mTOR抑制剂激活并放大自噬，受损的溶酶体阻止自噬体与自噬体的融合，自噬瘫痪，自噬体积累。因此，细胞内稳态被细胞器间网络破坏而无法通过自噬进行自我修复，从而引发泛光过程，并导致体外和体内显著的抗肿瘤治疗效果。该策略证明了干扰亚细胞胞间串扰的无毒纳米材料的选择性细胞毒性，为设计肿瘤治疗方法提供了一种新方法。

附：英文原文

Title: Fullerenols hijack lysosomes to disrupt inter-organellar crosstalk and block autophagy pre-activated by mTOR inhibitors for cancer cell PANoptosis

Author: Xue Li a c, Chunru Wang a c

Issue&Volume: 2025/02/25

Abstract: Subcellular inter-organellar crosstalk among lysosome, endoplasmic reticulum (ER), and mitochondrion is crucial for cancer cell survival and is a promising target in cancer treatment; however, efficiently disrupting these interactive networks is challenging. Herein, a communication interception strategy is presented, which specifically disrupts inter-organellar crosstalk by lysosomal contents leakage along with their trajectory and pre-activates autophagic flux to augment the lysosome-associated autophagy blocking for preventing the self-repair of this subcellular disorder. Briefly, fullerenols containing multiple hydroxyl groups (MF) tear the lysosomal phospholipid membrane through direct interaction, which causes lysosomal contents (calcium ions and cathepsins) to leak into the cytoplasm, subsequently leading to endoplasmic reticulum stress and mitochondrial dysfunction with redox imbalance and metabolic reprogramming. mTOR inhibitors activate and amplify autophagy, then impaired lysosomes prevent their fusion with autophagosome, and thus autophagy is paralyzed along with autolysosome accumulation. Consequently, the cellular homeostasis is compromised by destroyed inter-organellar networks without self-repair by autophagy, thereby triggering PANoptotic processes and leading to a remarkable anti-tumor therapeutic efficacy in vitro and in vivo. This strategy demonstrates the selective cytotoxicity of non-toxic nanomaterials that interfere with subcellular inter-organellar crosstalk, offering a novel method for designing tumor therapies.

DOI: 10.1016/j.scib.2025.02.034

Source: https://www.sciencedirect.com/science/article/pii/S2095927325002002