Self-Assembly of Short Peptides Activates Specific ER-Phagy and Induces Pyroptosis for Enhanced Tumor Immunotherapy

Developing specific endoplasmic reticulum-autophagy (ER-phagy) inducers is highly desirable for discovering new ER-phagy receptors and elucidating the detailed ER-phagy mechanism and potential cancer immunotherapy. However, most of the current ER-phagy-inducing methods cause nonselective autophagy of other organelles. In this work, we report the design and synthesis of simple and stable short peptides (D-FFxFFs) that could specifically trigger ER-phagy, which further induces pyroptosis and activates the immune response against tumor cells. D-FFxFFs locate preferentially in ER and readily self-assemble to form nanosized misfolded protein mimics, which lead to distinct upregulation of dedicated ER-phagy receptors with no obvious autophagy of other organelles. Significant unfolded protein response (UPR) is activated via IRE1-JNK and PERK-ATF4 pathways. Interestingly, the persistent ER-phagy triggers ER Ca²⁺ release and a surge in mitochondrial Ca²⁺ levels, resulting in GSDMD-mediated pyroptosis other than apoptosis. The ER-phagy induces pyroptosis and activates a distinct antitumor immune response without evolving the acquired drug resistance. This work not only provides a powerful tool for investigating the mechanism and function of ER-phagy but also offers an appealing strategy for anticancer immunotherapy.