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.Copyright © 2025 Science China Press. Published by Elsevier B.V. All rights reserved.