Supramolecular Self‐assembled Endoplasmic Reticulum‐Targeted Peptide Synergistically Triggers Type II ICD via Cascade Generation of Endogenous ROS and RNS for Cancer Immunotherapy

Abstract Endoplasmic reticulum (ER) stress triggered by reactive oxygen species (ROS) generated through photodynamic therapy emerges as an effective strategy for inducing immunogenic cell death (ICD). However, its therapeutic potential is often constrained by hypoxia and elevated glutathione levels in the tumor. Here, a novel ER‐targeted self‐assembled chimeric peptide, OTBS‐FR‐ER, which synergistically induces type II ICD via cascade generation of ROS and reactive nitrogen species (RNS) at the ER site is presented. The peptide contains an aggregation‐induced emission (AIE) photosensitizer (OTBS), a β‐amyloid‐inspired self‐assembly motif (FFVLK), an oligo‐arginine nitric oxide (NO) donor (RRRR), and an ER‐targeting signal (KDEL), which self‐assembles to form nanofibers in situ after targeting the ER and generates ROS to induce ER stress in response to photo‐irradiation. Simultaneously, ROS‐driven NO generation and subsequent formation of peroxynitrite anion (ONOO⁻) further amplify ER stress. In prostate cancer models, OTBS‐FR‐ER effectively converts immunogenic “cold” tumors into “hot” tumors, significantly activating the body's anti‐tumor immunity. Comprehensive in vitro and in vivo studies highlight its superior tumor inhibition and immune activation capabilities. This work provides a novel strategy for designing photo‐controlled type II ICD inducers, offering a promising direction to overcome the limitations of conventional tumor immunotherapies.