An Endoplasmic Reticulum Stress‐Specific Nanoinducer Selectively Evokes Type‐II Immunogenic Cell Death for Pyroptotic Cancer Immunotherapy

Abstract Specific induction of endoplasmic reticulum (ER) stress‐initiated type‐II immunogenic cell death (ICD) shows great potential in boosting tumor immunogenicity and anti‐tumor immunotherapy. However, it remains challenging to selectively provoke type‐II ICD, due to the lack of highly efficient ER targeting strategy. Here, a pH/Cathepsin‐Activatable Nanoplatform (PCAN) is reported to specifically photo‐induce ER stress (PCAN^ER) and type‐II ICD for cancer immunotherapy. PCAN^ER integrates the long‐circulating properties of nanomedicines with pH/cathepsin B dual‐gated design, exhibiting excellent ER targeting with a colocalization efficacy of 83% in cancer tissues. Through directly intensifying glucose‐regulated protein 78 and calreticulin exposure, PCAN^ER augments type‐II ICD and pyroptotic cancer cell death with high immune priming to cascade‐amplify the cancer‐immunity cycle, while the mild type‐I ICD induced by lysosome stress (PCAN^Ly) exhibits negligible antitumor efficacy. By leveraging the spatiotemporal subcellular organelle targeting of PCAN technology, this study achieves precise tuning of the type of ICD and cellular pyroptosis‐based cancer therapy. This study offers new insights into the design of organelle level‐targeted nanomedicines, paving the way for dissecting and modulating the cell death mechanism to boost cancer immunotherapy.