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-TER　(4,4′,4″,4′″-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(2-((4-methylphenyl)sulfonamido)ethyl)benzamide).　The　resulting　Ds-sP/TCPP-TER　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.　Copyright　©　2020　American　Chemical　Society.