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

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.