Endoplasmic Reticulum Targeting to Amplify Immunogenic Cell Death for Cancer Immunotherapy

Immunogenic cell death (ICD) elicited by photodynamic therapy (PDT) is mediated through generation of reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress. However, the half-life of ROS is very short and the intracellular diffusion depth is limited, which impairs ER localization and thus limits ER stress induction. To solve the problem, we synthesized reduction-sensitive Ds-sP NPs (PEG-s-s-1,2-distearoyl-<i>sn</i>-glycero-3-phosphoethanolamine-<i>N</i>-[amino(polyethylene glycol)-2000] nanoparticles) loaded with an efficient ER-targeting photosensitizer TCPP-T^ER (4,4',4″,4'″-(porphyrin-5,10,15,20-tetrayl)tetrakis(<i>N</i>-(2-((4-methylphenyl)sulfonamido)ethyl)benzamide). The resulting Ds-sP/TCPP-T^ER NPs could selectively accumulate in the ER and locally generate ROS under near-infrared (NIR) laser irradiation, which induced ER stress, amplified ICD, and activated immune cells, leading to augmented immunotherapy effect. This study presents a novel ICD amplifying, ER-targeting PDT strategy that can effectively eradicate primary tumors under NIR exposure, as well as distant tumors through an abscopal effect.