Endoplasmic Reticulum Targeting to Amplify Immunogenic Cell Death for Cancer Immunotherapy

Immunogenic cell death (ICD) elicited by photo-dynamic 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-sn-glycero-3-phosphoethanolamine-N[amino-(polyethylene glycol)-2000] nanoparticles) loaded with an efficient ER-targeting photosensitizer TCPP-T ER (4,4',4 '',4'"-(porphyrin-5,10,15,20-tetrayOtetrakis(N-(24(4-methylphenyOsulfonamido)-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.