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

Jiazhe Liu, Ruoyao Zhang, Yixuan Bao, Yijun Chen, Wenfang Zheng, Jianing Yuan, Zhuomiao Zhang, Pu Chen, Meiju Ji, Yangyang Cheng*, Peng Hou*, Dongfeng Dang, Dan Ding, Chao Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalAdvanced Functional Materials
DOIs
Publication statusAccepted/In press - 2025

Keywords

  • aggregation-induced emission
  • immunotherapy
  • mitochondrial targeting
  • PD-L1 degradation
  • photosensitizers

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Liu, J., Zhang, R., Bao, Y., Chen, Y., Zheng, W., Yuan, J., Zhang, Z., Chen, P., Ji, M., Cheng, Y., Hou, P., Dang, D., Ding, D., & Chen, C. (Accepted/In press). Highly Efficient and Universal Degradation of PD-L1 via Mitochondrial Oxidative Stress Evoked by Cationic AIE-Active Photosensitizers for Cancer Immunotherapy. Advanced Functional Materials. https://doi.org/10.1002/adfm.202414495