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

自噬 串扰 PI3K/AKT/mTOR通路 细胞生物学 癌症研究 癌细胞 化学 生物 癌症 信号转导 工程类 细胞凋亡 生物化学 遗传学 电子工程
作者
Hedong Qi,Xue Li,Jing Ma,Jiacheng Sun,Yating Liu,Xin Wang,Kelong Fan,Chunying Shu,Chunru Wang
出处
期刊:Science Bulletin [Elsevier BV]
标识
DOI:10.1016/j.scib.2025.02.034
摘要

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.
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