Hypoxia‐Activated Radical Anions to Trigger Reactive Oxygen Species Burst for Chemoimmunotherapy

ABSTRACT It is an effective strategy to induce immunogenic cell death (ICD) by utilizing the reactive oxygen species (ROS) generated in mitochondria to trigger endoplasmic reticulum stress. Electron‐deficient perylene diimide (PDI) is considered an ideal ROS inducer. In this paper, diethylamino‐modified dibromo‐substituted PDI (PBEA) and tetrachloro‐substituted PDI (PCEA) with mitochondrial localizing functions were designed as ROS inducers. In hypoxic tumors, PDI can gain electrons to generate PDI radical anion (PDI •− ), which will transfer electrons to oxygen to induce ROS generation, breaking the mitochondrial redox homeostasis and triggering ICD to initiate the antitumor immune response. PCEA can generate more ROS due to its enhanced ability to transfer electrons. Therefore, PCEA nanoparticles (PCEA NPs) exhibit better antitumor effects than PBEA NPs. The antiangiogenic property of sorafenib (SRF) can enhance the hypoxic levels of tumors to promote the production of PDI •− . The combination of antiangiogenesis and hypoxia‐activated ICD inducers provides an innovative paradigm for tumor‐specific therapy.