Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors

Checkpoint blockade immunotherapy has emerged as a transformative approach in cancer treatment by activating tumor-infiltrating T cells. However, the efficacy of PD-L1 blockade is restricted in “cold” tumors, which are characterized by low immunogenicity, presenting a challenge to immunotherapy. Thi...

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Main Authors: Changyong Guo, Shipeng He, Huaxing Shen, Wei Cong, Jinqiu Li, Yajing Ji, Wenjing Huang, Fei Gao, Honggang Hu
Format: Article
Language:English
Published: Elsevier 2025-07-01
Series:Acta Pharmaceutica Sinica B
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Online Access:http://www.sciencedirect.com/science/article/pii/S2211383525003296
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author Changyong Guo
Shipeng He
Huaxing Shen
Wei Cong
Jinqiu Li
Yajing Ji
Wenjing Huang
Fei Gao
Honggang Hu
author_facet Changyong Guo
Shipeng He
Huaxing Shen
Wei Cong
Jinqiu Li
Yajing Ji
Wenjing Huang
Fei Gao
Honggang Hu
author_sort Changyong Guo
collection DOAJ
description Checkpoint blockade immunotherapy has emerged as a transformative approach in cancer treatment by activating tumor-infiltrating T cells. However, the efficacy of PD-L1 blockade is restricted in “cold” tumors, which are characterized by low immunogenicity, presenting a challenge to immunotherapy. This study introduces an innovative strategy, utilizing cathepsin-cleavable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-assisted combined photodynamic therapy (PDT) and PD-L1 degradation for the first time, effectively treating T cell-deficient tumors. The degradable main-chain polymer, conjugated with photosensitizer porphyrin, facilitates the accumulation of reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and promoting cytotoxic T lymphocytes (CTLs) infiltration into tumors. Multivalent peptide antagonists of PD-L1 promote PD-L1 degradation in lysosomes through receptor crosslinking, overcoming the adaptive cycling of PD-L1 to the tumor cell surface. These findings demonstrate that polymer-assisted PDT and PD-L1 crosslinking degradation represent a potential novel strategy for anti-tumor immunotherapy, providing valuable tools for expanding immunotherapy applications in immunosuppressive cancers.
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institution Matheson Library
issn 2211-3835
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publishDate 2025-07-01
publisher Elsevier
record_format Article
series Acta Pharmaceutica Sinica B
spelling doaj-art-7e546d0da23145859b3fa6ee1e39e89f2025-07-09T04:32:17ZengElsevierActa Pharmaceutica Sinica B2211-38352025-07-0115738053818Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumorsChangyong Guo0Shipeng He1Huaxing Shen2Wei Cong3Jinqiu Li4Yajing Ji5Wenjing Huang6Fei Gao7Honggang Hu8School of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaCorresponding authors.; School of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaSchool of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaSchool of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaSchool of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaSchool of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaSchool of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaCorresponding authors.; School of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaCorresponding authors.; School of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, ChinaCheckpoint blockade immunotherapy has emerged as a transformative approach in cancer treatment by activating tumor-infiltrating T cells. However, the efficacy of PD-L1 blockade is restricted in “cold” tumors, which are characterized by low immunogenicity, presenting a challenge to immunotherapy. This study introduces an innovative strategy, utilizing cathepsin-cleavable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-assisted combined photodynamic therapy (PDT) and PD-L1 degradation for the first time, effectively treating T cell-deficient tumors. The degradable main-chain polymer, conjugated with photosensitizer porphyrin, facilitates the accumulation of reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and promoting cytotoxic T lymphocytes (CTLs) infiltration into tumors. Multivalent peptide antagonists of PD-L1 promote PD-L1 degradation in lysosomes through receptor crosslinking, overcoming the adaptive cycling of PD-L1 to the tumor cell surface. These findings demonstrate that polymer-assisted PDT and PD-L1 crosslinking degradation represent a potential novel strategy for anti-tumor immunotherapy, providing valuable tools for expanding immunotherapy applications in immunosuppressive cancers.http://www.sciencedirect.com/science/article/pii/S2211383525003296ImmunotherapyPD-L1Photodynamic therapyProtein degradationPolymerImmunogenic cell death
spellingShingle Changyong Guo
Shipeng He
Huaxing Shen
Wei Cong
Jinqiu Li
Yajing Ji
Wenjing Huang
Fei Gao
Honggang Hu
Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors
Acta Pharmaceutica Sinica B
Immunotherapy
PD-L1
Photodynamic therapy
Protein degradation
Polymer
Immunogenic cell death
title Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors
title_full Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors
title_fullStr Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors
title_full_unstemmed Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors
title_short Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors
title_sort polymer assisted pd l1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors
topic Immunotherapy
PD-L1
Photodynamic therapy
Protein degradation
Polymer
Immunogenic cell death
url http://www.sciencedirect.com/science/article/pii/S2211383525003296
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