TY - JOUR
T1 - Highly Efficient and Universal Degradation of PD-L1 via Mitochondrial Oxidative Stress Evoked by Cationic AIE-Active Photosensitizers for Cancer Immunotherapy
AU - Liu, Jiazhe
AU - Zhang, Ruoyao
AU - Bao, Yixuan
AU - Chen, Yijun
AU - Zheng, Wenfang
AU - Yuan, Jianing
AU - Zhang, Zhuomiao
AU - Chen, Pu
AU - Ji, Meiju
AU - Cheng, Yangyang
AU - Hou, Peng
AU - Dang, Dongfeng
AU - Ding, Dan
AU - Chen, Chao
N1 - Publisher Copyright:
© 2025 Wiley-VCH GmbH.
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
KW - aggregation-induced emission
KW - immunotherapy
KW - mitochondrial targeting
KW - PD-L1 degradation
KW - photosensitizers
UR - http://www.scopus.com/inward/record.url?scp=85215288657&partnerID=8YFLogxK
U2 - 10.1002/adfm.202414495
DO - 10.1002/adfm.202414495
M3 - Article
AN - SCOPUS:85215288657
SN - 1616-301X
JO - Advanced Functional Materials
JF - Advanced Functional Materials
ER -