21:T493,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-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-tetrayl)tetrakis(N-(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.22:T4e4,Immunogenic cell death (ICD), a manner of tumor cell death that can trigger antitumor immune responses, has received extensive attention as a potential synergistic modality for cancer immunotherapy. Although many calcium ion (Ca²⁺) nanomodulators have been developed for cancer therapy through mitochondrial Ca²⁺ overload, their ICD-inducing properties have not been explored. Herein, an acid-sensitive PEG-decorated calcium carbonate (CaCO₃) nanoparticle incorporating curcumin (CUR; a Ca²⁺ enhancer) (^PEGCaCUR) was prepared using a simple one-pot strategy. ^PEGCaCUR served as not only a Ca²⁺ nanomodulator inducing efficient mitochondrial Ca²⁺ overload but also an ICD inducer during improved synergistic cancer therapy. Combination of ^PEGCaCUR with ultrasound (US), ^PEGCaCUR+US, led to an enhanced ICD effect attributable to the enhanced mitochondrial Ca²⁺ overload, along with subsequent upregulation of reactive oxygen species levels. ^PEGCaCUR also facilitates photoacoustic/fluorescence dual-mode imaging, as well as effectively suppressing tumor growth and metastasis, indicating promising theranostic properties.

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