An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancer
The clinical potency of anti-programmed death-ligand 1 (PD-L1) therapy in metastatic triple-negative breast cancer (TNBC) is modest primarily because of the intrinsic low immunogenicity and an immunosuppressive tumor microenvironment (TME). Photodynamic therapy (PDT), an inducer of immunogenic cell...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-07-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1651165/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839626592146423808 |
|---|---|
| author | Yuetong Liu Yuetong Liu Yuetong Liu Liming Wang Feiyan Kong Tianjun Liu Hong Liu Hong Liu Hong Liu |
| author_facet | Yuetong Liu Yuetong Liu Yuetong Liu Liming Wang Feiyan Kong Tianjun Liu Hong Liu Hong Liu Hong Liu |
| author_sort | Yuetong Liu |
| collection | DOAJ |
| description | The clinical potency of anti-programmed death-ligand 1 (PD-L1) therapy in metastatic triple-negative breast cancer (TNBC) is modest primarily because of the intrinsic low immunogenicity and an immunosuppressive tumor microenvironment (TME). Photodynamic therapy (PDT), an inducer of immunogenic cell death (ICD), has the potential to enhance antitumor immune response and improve PD-L1 blockade efficacy. DTP, a novel photosensitizer developed previously, has demonstrated potent ROS-dependent photocytotoxicity, yet its immunomodulatory effects remain unexplored. This study investigated the induction of ICD and dendritic cell (DC) maturation following DTP-PDT in vivo and in vitro. A bilateral TNBC model was developed to assess the efficacy of DTP-PDT combined with α-PD-L1 therapy on untreated distant tumors and to explore its potential immunological mechanisms. The results showed that DTP-PDT effectively induced ICD, demonstrated by calreticulin membrane exposure, high mobility group box 1 protein release, and increased secretion of interferon-γ and tumor necrosis factor-α, resulting in DC maturation. The combination of DTP-PDT and α-PD-L1 significantly inhibited distant tumor growth. This effect was associated with increased CD8+ and CD4+ T cells infiltration, and reduced numbers of regulatory T cells, in the distant tumor and spleen. In conclusion, DTP-PDT enhanced TNBC sensitivity to α-PD-L1 by inducing ICD, and its combination withα-PD-L1 could remodel the immunosuppressive TME and enhance systemic immunity, resulting in a therapeutic effect against distant metastasis. This study provides experimental validation for a combined strategy of DTP-PDT and α-PD-L1, proposing a potential therapeutic approach for metastatic TNBC. |
| format | Article |
| id | doaj-art-d2dcc0cedaae42f0a0697c0ae9b596aa |
| institution | Matheson Library |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-d2dcc0cedaae42f0a0697c0ae9b596aa2025-07-17T05:24:12ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-07-011610.3389/fphar.2025.16511651651165An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancerYuetong Liu0Yuetong Liu1Yuetong Liu2Liming Wang3Feiyan Kong4Tianjun Liu5Hong Liu6Hong Liu7Hong Liu8The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, ChinaTianjin’s Clinical Research Center for Cancer, Tianjin, ChinaKey Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University, Tianjin, ChinaState Key Laboratory of Component-Based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis and Research Center, Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaSchool of Basic Medical Sciences, Hebei University, Baoding, ChinaState Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, ChinaThe Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, ChinaTianjin’s Clinical Research Center for Cancer, Tianjin, ChinaKey Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University, Tianjin, ChinaThe clinical potency of anti-programmed death-ligand 1 (PD-L1) therapy in metastatic triple-negative breast cancer (TNBC) is modest primarily because of the intrinsic low immunogenicity and an immunosuppressive tumor microenvironment (TME). Photodynamic therapy (PDT), an inducer of immunogenic cell death (ICD), has the potential to enhance antitumor immune response and improve PD-L1 blockade efficacy. DTP, a novel photosensitizer developed previously, has demonstrated potent ROS-dependent photocytotoxicity, yet its immunomodulatory effects remain unexplored. This study investigated the induction of ICD and dendritic cell (DC) maturation following DTP-PDT in vivo and in vitro. A bilateral TNBC model was developed to assess the efficacy of DTP-PDT combined with α-PD-L1 therapy on untreated distant tumors and to explore its potential immunological mechanisms. The results showed that DTP-PDT effectively induced ICD, demonstrated by calreticulin membrane exposure, high mobility group box 1 protein release, and increased secretion of interferon-γ and tumor necrosis factor-α, resulting in DC maturation. The combination of DTP-PDT and α-PD-L1 significantly inhibited distant tumor growth. This effect was associated with increased CD8+ and CD4+ T cells infiltration, and reduced numbers of regulatory T cells, in the distant tumor and spleen. In conclusion, DTP-PDT enhanced TNBC sensitivity to α-PD-L1 by inducing ICD, and its combination withα-PD-L1 could remodel the immunosuppressive TME and enhance systemic immunity, resulting in a therapeutic effect against distant metastasis. This study provides experimental validation for a combined strategy of DTP-PDT and α-PD-L1, proposing a potential therapeutic approach for metastatic TNBC.https://www.frontiersin.org/articles/10.3389/fphar.2025.1651165/fullphotodynamic therapyimmunogenic cell deathmetastatic triple-negative breast cancerprogrammed death-ligand 1 blockadeabscopal effectsystemic antitumor immunity |
| spellingShingle | Yuetong Liu Yuetong Liu Yuetong Liu Liming Wang Feiyan Kong Tianjun Liu Hong Liu Hong Liu Hong Liu An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancer Frontiers in Pharmacology photodynamic therapy immunogenic cell death metastatic triple-negative breast cancer programmed death-ligand 1 blockade abscopal effect systemic antitumor immunity |
| title | An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancer |
| title_full | An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancer |
| title_fullStr | An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancer |
| title_full_unstemmed | An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancer |
| title_short | An immunomodulatory photosensitizer-mediated photodynamic therapy synergizes with PD-L1 blockade against metastatic triple-negative breast cancer |
| title_sort | immunomodulatory photosensitizer mediated photodynamic therapy synergizes with pd l1 blockade against metastatic triple negative breast cancer |
| topic | photodynamic therapy immunogenic cell death metastatic triple-negative breast cancer programmed death-ligand 1 blockade abscopal effect systemic antitumor immunity |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1651165/full |
| work_keys_str_mv | AT yuetongliu animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT yuetongliu animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT yuetongliu animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT limingwang animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT feiyankong animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT tianjunliu animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT hongliu animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT hongliu animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT hongliu animmunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT yuetongliu immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT yuetongliu immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT yuetongliu immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT limingwang immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT feiyankong immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT tianjunliu immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT hongliu immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT hongliu immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer AT hongliu immunomodulatoryphotosensitizermediatedphotodynamictherapysynergizeswithpdl1blockadeagainstmetastatictriplenegativebreastcancer |