An ER stress and mitochondrial apoptosis Co-inducer for enhanced cancer immunotherapy

Though immunogenic cell death (ICD) has garnered significant attention in the realm of anticancer therapies, effectively stimulating strong immune responses with adequate antigen presentation in deep-seated cancers remains challenging. Herein, to promote antigen presentation, an efficient dual-targeted photodynamic ICD inducer is developed. Due to the enhanced spin-orbit coupling and electron structure modulation, the Cy5-I-CF₃ probe showcases exceptional reactive oxygen species (ROS) generation capacity within cancer cells. The Cy5-I-CF₃ also displays the co-targeting ability toward the endoplasmic reticulum (ER) and mitochondria. More importantly, the in-situ ROS generation synergistically facilitates the interaction between ER and mitochondria, thereby invoking a more robust ER stress response through cascade amplification mechanisms, resulting in substantial release of damage-associated molecular patterns (DAMPs) and strong induction of ICD. This augmentation ultimately enhances the endogenous antigen presentation machinery. Adequate antigen presentation promotes the dendritic cell (DC) maturation and infiltration of cytotoxic T lymphocytes (CTLs) to realize efficient immunotherapy. As a result, Cy5-I-CF₃ notably restrains the growth of distant and primary cancers by photodynamic-induced immunotherapy. Our research offers valuable insights for the design of efficacious ICD inducers, advancing the utilization of cancer immunotherapy.