Oxidative Stress Amplifiers as Immunogenic Cell Death Nanoinducers Disrupting Mitochondrial Redox Homeostasis for Cancer Immunotherapy.

Reactive oxygen species (ROS)-induced oxidative stress in the endoplasmic reticulum (ER) is generally believed to be an important prerequisite for immunogenic cell death (ICD) which can trigger antitumor immune responses for cancer immunotherapy. However, thus far, little is known between the oxidative stress in a certain organelle other than ER and ICD. Herein, polymers for preparing ROS-responsive nanoparticles (NP-I-CA-TPP) with mitochondrial targeting performance as ICD nanoinducers are designed. It is believed that NP-I-CA-TPP can target mitochondria which are extremely important organelles intimately involved in cellular stress signaling to play an important role in the induction of ICD. NP-I-CA-TPP can amplify cinnamaldehyde (CA)-induced ROS damage by iodo-thiol click chemistry-mediated glutathione depletion in cancer cells. Finally, NP-I-CA-TPP is shown to disrupt mitochondrial redox homeostasis, amplify mitochondrial oxidative stress, promote cancer cell apoptosis via inducing ICD, and triggering the body's antitumor immune response for cancer immunotherapy.