Polymer-assisted PD-L1 degradation and targeted photodynamic therapy synergize to suppress immunodeficient tumors.
10.1016/j.apsb.2025.05.022
- Author:
Changyong GUO
1
;
Shipeng HE
1
;
Huaxing SHEN
1
;
Wei CONG
1
;
Jinqiu LI
1
;
Yajing JI
1
;
Wenjing HUANG
1
;
Fei GAO
1
;
Honggang HU
1
Author Information
1. School of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, China.
- Publication Type:Journal Article
- Keywords:
Cytotoxic T lymphocytes;
Immunogenic cell death;
Immunotherapy;
PD-L1;
Photodynamic therapy;
Polymer;
Protein degradation;
Reactive oxygen species
- From:
Acta Pharmaceutica Sinica B
2025;15(7):3805-3818
- CountryChina
- Language:English
-
Abstract:
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.
