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...
Saved in:
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2025-07-01
|
Series: | Acta Pharmaceutica Sinica B |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525003296 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
_version_ | 1839635684275519488 |
---|---|
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. |
format | Article |
id | doaj-art-7e546d0da23145859b3fa6ee1e39e89f |
institution | Matheson Library |
issn | 2211-3835 |
language | English |
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 |
work_keys_str_mv | AT changyongguo polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT shipenghe polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT huaxingshen polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT weicong polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT jinqiuli polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT yajingji polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT wenjinghuang polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT feigao polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors AT hongganghu polymerassistedpdl1degradationandtargetedphotodynamictherapysynergizetosuppressimmunodeficienttumors |