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

Abstract 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 Ca 2+ release and a surge in mitochondrial Ca 2+ 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.