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

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.

Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy.

Cancer progression and treatment-associated cellular stress impairs therapeutic outcome by inducing resistance. Endoplasmic reticulum (ER) stress is responsible for core events. Aberrant activation of stress sensors and their downstream components to disrupt homeostasis have emerged as vital regulators of tumor progression as well as response to cancer therapy. Here, an orchestrated nanophotoinducer (ERsNP) results in specific tumor ER-homing, induces hyperthermia and mounting oxidative stress associated reactive oxygen species (ROS), and provokes intense and lethal ER stress upon near-infrared laser irradiation. The strengthened "dying" of ER stress and ROS subsequently induce apoptosis for both primary and abscopal B16F10 and GL261 tumors, and promote damage-associated molecular patterns to evoke stress-dependent immunogenic cell death effects and release "self-antigens". Thus, there is a cascade to activate maturation of dendritic cells, reprogram myeloid-derived suppressor cells to manipulate immunosuppression, and recruit cytotoxic T lymphocytes and effective antitumor response. The long-term protection against tumor recurrence is realized through cascaded combinatorial preoperative and postoperative photoimmunotherapy including the chemokine (C-C motif) receptor 2 antagonist, ERsNP upon laser irradiation, and an immune checkpoint inhibitor. The results highlight great promise of the orchestrated nanophotoinducer to exert potent immunogenic cell stress and death by reinforcing ER stress and oxidative stress to boost cancer photoimmunotherapy.