Highly Efficient and Universal Degradation of PD‐L1 via Mitochondrial Oxidative Stress Evoked by Cationic AIE‐Active Photosensitizers for Cancer Immunotherapy

Abstract The blockade of interactions between programmed death‐ligand 1 (PD‐L1) on cancer cell surfaces and programmed cell death‐1 (PD‐1) receptors on T cells is a crucial strategy in cancer immunotherapy. However, the continuous replenishment of PD‐L1 from intracellular stores presents a significant challenge that undermines therapeutic efficacy. Therefore, effective downregulation of intracellular PD‐L1 is essential for improving treatment outcomes. In this study, a novel approach that utilizes mitochondrial oxidative stress to achieve highly efficient and universal PD‐L1 degradation is presented. A cationic aggregation‐induced emission‐active photosensitizer, DPA‐B‐YP + , which generates reactive oxygen species (ROS) upon light activation to induce mitochondrial oxidative stress on demand is developed. Compared to traditional high‐performance PD‐L1 degraders such as metformin and berberine, ROS‐induced mitochondrial stress by DPA‐B‐YP + demonstrates superior efficiency and broader applicability in PD‐L1 degradation across various tumor types. Mechanistic studies reveal that PD‐L1 degradation by DPA‐B‐YP + occurs via the AMPK‐ubiquitination pathway. Furthermore, in a murine immunogenic “cold” tumor model, DPA‐B‐YP + effectively degrades PD‐L1 and significantly enhances CD8 + T cell‐mediated immune responses upon light activation, without the need for additional drugs or immune adjuvants. These findings present a novel approach and material for PD‐L1 degradation, contributing to advancements in cancer immunotherapy.