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.