An Endoplasmic Reticulum‐Targeting and Calcium Metabolism‐Disrupting Nanodrug Enhances Tumor Photodynamic Immunotherapy

Abstract The inefficient clearance of deep tumors and metastatic lesions greatly hinders the clinical applications of photodynamic therapy (PDT). Inducing robust immunogenic cell death (ICD) is crucial for improving PDT outcomes, as ICD‐mediated T‐cell adaptive immune responses suppress tumor recurrence and metastasis. Sustained endoplasmic reticulum (ER) stress is essential for activating ICD, however, inadequate photosensitizer enrichment in the ER and cell‐protective mechanisms, such as the unfolded protein response (UPR) and antioxidant defense, often result in insufficient ER stress and ineffective ICD. To overcome these challenges, PPRK@MTO, a nanodrug co‐assembled from ER‐targeting chimeric peptide PpIX‐PEG₈‐RKR‐KDEL (PPRK) and mitochondrial calcium uniporter (MCU) inhibitor mitoxantrone (MTO) is developed. Upon laser irradiation, PPRK generates reactive oxygen species (ROS) in situ, inducing strong ER stress and promoting ICD. Meanwhile, MTO inhibits MCU, reducing mitochondrial calcium influx and energy supply for UPR and glutathione biosynthesis, thereby amplifying PDT efficacy and enhancing ICD, inducing a strong antitumor immune response. PPRK@MTO demonstrats potent tumor suppression in vivo and prolonged survival in 4T1 tumor‐bearing mice with a single administration. This ER‐targeting and mitochondrial metabolism‐disrupting nanodrug provides a promising strategy for high‐efficiency photodynamic immunotherapy.