Endoplasmic Reticulum Stress Nano‐Orchestrators for Precisely Regulated Immunogenic Cell Death as Potent Cancer Vaccines

Abstract Dying tumor cells regulated by immunogenic cell death (ICD) inducers are promising candidates for cancer vaccine development because of their comprehensive antigen spectrum. However, their limited immunogenicity and potential tumorigenicity hinder clinical translation. To address these challenges, a nano‐orchestrator is developed that targets the endoplasmic reticulum (ER) stress, a critical pre‐ICD event, to optimize the “precise dose” of ER stress. Using a clinical‐range irradiation fluence (50‒200 J cm −2 ) with an 808 nm laser, the release of damage associated molecular patterns (DAMPs) and antigens are precisely regulated. A fluence of 150 J cm −2 (2 W cm −2 for 75 s) increases dendritic cell maturation and antitumor T cell proliferation, providing valuable clinical insights. The ER stress nano‐orchestrator enhances both adjuvanticity and antigenicity via the protein kinase R‐like endoplasmic reticulum kinase (PERK)‐C/EBP homologous protein (CHOP) pathway to regulate ICD‐induced DAMPs and promote tumor cell apoptosis. These optimized ER stress phototherapeutic dying tumor cells can serve as prophylactic vaccines, achieving a remarkable 100% success rate against tumor rechallenge in vivo. Additionally, the nano‐orchestrator shows the potential to develop in situ therapeutic tumor vaccines when combined with anti‐PD‐L1 treatment, providing important insights into enhancing the efficacy of immune checkpoint regulators by modulating endogenous immune responses.