A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition
Abstract Photodynamic therapy (PDT) is a promising cancer therapy modality by generating reactive oxygen species (ROS) and triggering immunogenic cell death. However, the therapeutic effect of PDT is strongly limited by tumor hypoxia and immunosuppressive landscape. Herein, a pH‐sensitive nanosized...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-08-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202504860 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849391249728995328 |
|---|---|
| author | Lei Lei Wenbin Dai Jinchao Zhao Angfeng Jiang Haisheng Peng Qiao Jin Xiaojing Li Zhe Tang |
| author_facet | Lei Lei Wenbin Dai Jinchao Zhao Angfeng Jiang Haisheng Peng Qiao Jin Xiaojing Li Zhe Tang |
| author_sort | Lei Lei |
| collection | DOAJ |
| description | Abstract Photodynamic therapy (PDT) is a promising cancer therapy modality by generating reactive oxygen species (ROS) and triggering immunogenic cell death. However, the therapeutic effect of PDT is strongly limited by tumor hypoxia and immunosuppressive landscape. Herein, a pH‐sensitive nanosized covalent–organic polymer (COP), composed of the photosensitizer porphyrin and pyruvate kinase inhibitor vitamin K3 (VK3), is designed to overcome these issues. The signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 is further encapsulated into COPs to form a WP1066‐loaded COP (TVW). As an inhibitor of pyruvate kinase, VK3 can reduce intracellular oxygen consumption by inhibiting the glycolytic pathway, leading to the alleviation of the tumor hypoxic microenvironment. The relief of tumor hypoxia by VK3 enhances photodynamic cytotoxicity by generating more ROS. Meanwhile, STAT3 acts as a major regulator of PD‐L1, a key inhibitor that promotes immune escape. WP1066 effectively inhibits the expression of STAT3 and reduces PD‐L1 expression, thereby significantly inhibiting tumor immune escape and enhancing antitumor efficacy in a synergistic manner. The antitumor capacity of photodynamic immunotherapy is extensively investigated in a murine subcutaneous hepatocellular carcinoma model. This photo‐immunotherapy may provide an effective combination regimen for the efficient treatment of solid tumors such as hepatocellular carcinoma. |
| format | Article |
| id | doaj-art-1d0c5bead94f4132afcc8b8bd78a9a34 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-1d0c5bead94f4132afcc8b8bd78a9a342025-08-20T03:41:08ZengWileyAdvanced Science2198-38442025-08-011229n/an/a10.1002/advs.202504860A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 InhibitionLei Lei0Wenbin Dai1Jinchao Zhao2Angfeng Jiang3Haisheng Peng4Qiao Jin5Xiaojing Li6Zhe Tang7Department of General Surgery The Fourth Affiliated Hospital International Institutes of Medicine Zhejiang University School of Medicine Yiwu 322000 ChinaMOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and Engineering Zhejiang University Hangzhou 310058 ChinaDepartment of General Surgery The Fourth Affiliated Hospital International Institutes of Medicine Zhejiang University School of Medicine Yiwu 322000 ChinaDepartment of General Surgery The Fourth Affiliated Hospital International Institutes of Medicine Zhejiang University School of Medicine Yiwu 322000 ChinaDepartment of Pharmacology Medical College of Shaoxing University Shaoxing 312099 ChinaMOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and Engineering Zhejiang University Hangzhou 310058 ChinaDepartment of Gynecology The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310058 ChinaDepartment of Surgery The Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310058 ChinaAbstract Photodynamic therapy (PDT) is a promising cancer therapy modality by generating reactive oxygen species (ROS) and triggering immunogenic cell death. However, the therapeutic effect of PDT is strongly limited by tumor hypoxia and immunosuppressive landscape. Herein, a pH‐sensitive nanosized covalent–organic polymer (COP), composed of the photosensitizer porphyrin and pyruvate kinase inhibitor vitamin K3 (VK3), is designed to overcome these issues. The signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 is further encapsulated into COPs to form a WP1066‐loaded COP (TVW). As an inhibitor of pyruvate kinase, VK3 can reduce intracellular oxygen consumption by inhibiting the glycolytic pathway, leading to the alleviation of the tumor hypoxic microenvironment. The relief of tumor hypoxia by VK3 enhances photodynamic cytotoxicity by generating more ROS. Meanwhile, STAT3 acts as a major regulator of PD‐L1, a key inhibitor that promotes immune escape. WP1066 effectively inhibits the expression of STAT3 and reduces PD‐L1 expression, thereby significantly inhibiting tumor immune escape and enhancing antitumor efficacy in a synergistic manner. The antitumor capacity of photodynamic immunotherapy is extensively investigated in a murine subcutaneous hepatocellular carcinoma model. This photo‐immunotherapy may provide an effective combination regimen for the efficient treatment of solid tumors such as hepatocellular carcinoma.https://doi.org/10.1002/advs.202504860covalent–organic polymerhypoxia reliefimmunotherapynanomedicinephotodynamic therapy |
| spellingShingle | Lei Lei Wenbin Dai Jinchao Zhao Angfeng Jiang Haisheng Peng Qiao Jin Xiaojing Li Zhe Tang A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition Advanced Science covalent–organic polymer hypoxia relief immunotherapy nanomedicine photodynamic therapy |
| title | A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition |
| title_full | A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition |
| title_fullStr | A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition |
| title_full_unstemmed | A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition |
| title_short | A pH‐Sensitive Nanosized Covalent–Organic Polymer for Enhanced Tumor Photodynamic Immunotherapy by Hypoxia Relief and STAT3 Inhibition |
| title_sort | ph sensitive nanosized covalent organic polymer for enhanced tumor photodynamic immunotherapy by hypoxia relief and stat3 inhibition |
| topic | covalent–organic polymer hypoxia relief immunotherapy nanomedicine photodynamic therapy |
| url | https://doi.org/10.1002/advs.202504860 |
| work_keys_str_mv | AT leilei aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT wenbindai aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT jinchaozhao aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT angfengjiang aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT haishengpeng aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT qiaojin aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT xiaojingli aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT zhetang aphsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT leilei phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT wenbindai phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT jinchaozhao phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT angfengjiang phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT haishengpeng phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT qiaojin phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT xiaojingli phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition AT zhetang phsensitivenanosizedcovalentorganicpolymerforenhancedtumorphotodynamicimmunotherapybyhypoxiareliefandstat3inhibition |