Molecular Recognition Driven Organelle Cross-Linking Induces Endoplasmic Reticulum Stress and Mitochondrial Dysfunction to Potentiate Cancer Immunotherapy.

Abstract

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.