Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist
Abstract Imiquimod (IMQ), a drug from aminoquinoline group, is the toll-like receptor 7 (TLR7) agonist. It acts as an immunostimulant and radio-sensitizing agent. IMQ stimulates both innate and adaptive immune response. Despite studies conducted, there are no unambiguous data showing how IMQ affects...
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| Format: | Article |
| Language: | English |
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Springer
2025-02-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-03943-2 |
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| author | Jarosz-Biej Magdalena Czapla Justyna Ciepła Joanna Smolarczyk Ryszard Drzyzga Alina Sprus-Lipka Dorota Pilny Ewelina Matuszczak Sybilla Cichoń Tomasz |
| author_facet | Jarosz-Biej Magdalena Czapla Justyna Ciepła Joanna Smolarczyk Ryszard Drzyzga Alina Sprus-Lipka Dorota Pilny Ewelina Matuszczak Sybilla Cichoń Tomasz |
| author_sort | Jarosz-Biej Magdalena |
| collection | DOAJ |
| description | Abstract Imiquimod (IMQ), a drug from aminoquinoline group, is the toll-like receptor 7 (TLR7) agonist. It acts as an immunostimulant and radio-sensitizing agent. IMQ stimulates both innate and adaptive immune response. Despite studies conducted, there are no unambiguous data showing how IMQ affects the condition of tumor blood vessels. Tumor vasculature plays the main role in tumor progression. Formation of abnormal blood vessels increases area of hypoxia which recruits suppressor cells, blocks tumor infiltration by CD8+ T lymphocytes, inhibits efficacy of chemoterapeutic drug and leads to cancer relapse. Normalization is a type of therapy targeted at abnormal tumor blood vessels. Here, we demonstrated that 50 µg of IMQ inhibits the growth of melanoma tumors more efficiently, compared to other tested doses and the control group. Dose escalation did not improve the therapeutic antitumor potential of TLR7 agonist. A dose of 50 µg of IMQ most effectively reduced tumor blood vessel density. Imiquimod normalized tumor vasculature both structurally (by reducing vessel tortuosity and increasing pericyte coverage) and functionally (by improving tumor perfusion) in a dose-dependent manner. Hypoxia regions in tumors of treated mice were significantly reduced after IMQ administration. A dose of 50 µg of IMQ had also the greatest impact on the changes in tumor-infiltrating T lymphocytes levels. TLR7 agonist inhibited angiogenesis in treated mice. Functional vascular normalization by IMQ increases the effectiveness of low dose of doxorubicin. Higher dose of IMQ showed worse effects than lower doses including decreased tumor perfusion, increased tumor hypoxia and immunosuppression. This knowledge may help to optimize the combination of the selected IMQ dose with e.g. chemotherapy or radiotherapy to elicit synergistic effect in cancer treatment. To conclude, we outline IMQ repurposing as a vascular normalizing agent. Our research results may contribute to expanding the therapeutic indications for the use of IMQ in anticancer therapy in the future. |
| format | Article |
| id | doaj-art-1bd7bac71f8d4b4386730659be15ecb8 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-1bd7bac71f8d4b4386730659be15ecb82025-02-02T12:26:18ZengSpringerCancer Immunology, Immunotherapy1432-08512025-02-0174311310.1007/s00262-025-03943-2Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonistJarosz-Biej Magdalena0Czapla Justyna1Ciepła Joanna2Smolarczyk Ryszard3Drzyzga Alina4Sprus-Lipka Dorota5Pilny Ewelina6Matuszczak Sybilla7Cichoń Tomasz8Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyCenter for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of OncologyAbstract Imiquimod (IMQ), a drug from aminoquinoline group, is the toll-like receptor 7 (TLR7) agonist. It acts as an immunostimulant and radio-sensitizing agent. IMQ stimulates both innate and adaptive immune response. Despite studies conducted, there are no unambiguous data showing how IMQ affects the condition of tumor blood vessels. Tumor vasculature plays the main role in tumor progression. Formation of abnormal blood vessels increases area of hypoxia which recruits suppressor cells, blocks tumor infiltration by CD8+ T lymphocytes, inhibits efficacy of chemoterapeutic drug and leads to cancer relapse. Normalization is a type of therapy targeted at abnormal tumor blood vessels. Here, we demonstrated that 50 µg of IMQ inhibits the growth of melanoma tumors more efficiently, compared to other tested doses and the control group. Dose escalation did not improve the therapeutic antitumor potential of TLR7 agonist. A dose of 50 µg of IMQ most effectively reduced tumor blood vessel density. Imiquimod normalized tumor vasculature both structurally (by reducing vessel tortuosity and increasing pericyte coverage) and functionally (by improving tumor perfusion) in a dose-dependent manner. Hypoxia regions in tumors of treated mice were significantly reduced after IMQ administration. A dose of 50 µg of IMQ had also the greatest impact on the changes in tumor-infiltrating T lymphocytes levels. TLR7 agonist inhibited angiogenesis in treated mice. Functional vascular normalization by IMQ increases the effectiveness of low dose of doxorubicin. Higher dose of IMQ showed worse effects than lower doses including decreased tumor perfusion, increased tumor hypoxia and immunosuppression. This knowledge may help to optimize the combination of the selected IMQ dose with e.g. chemotherapy or radiotherapy to elicit synergistic effect in cancer treatment. To conclude, we outline IMQ repurposing as a vascular normalizing agent. Our research results may contribute to expanding the therapeutic indications for the use of IMQ in anticancer therapy in the future.https://doi.org/10.1007/s00262-025-03943-2TLR7 agonistImiquimodAntiangiogenic therapyBlood vessels normalizationHypoxiaDrug repurposing |
| spellingShingle | Jarosz-Biej Magdalena Czapla Justyna Ciepła Joanna Smolarczyk Ryszard Drzyzga Alina Sprus-Lipka Dorota Pilny Ewelina Matuszczak Sybilla Cichoń Tomasz Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist Cancer Immunology, Immunotherapy TLR7 agonist Imiquimod Antiangiogenic therapy Blood vessels normalization Hypoxia Drug repurposing |
| title | Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist |
| title_full | Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist |
| title_fullStr | Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist |
| title_full_unstemmed | Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist |
| title_short | Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist |
| title_sort | normalization of tumor vasculature by imiquimod proposal for a new anticancer therapeutic indication for a tlr7 agonist |
| topic | TLR7 agonist Imiquimod Antiangiogenic therapy Blood vessels normalization Hypoxia Drug repurposing |
| url | https://doi.org/10.1007/s00262-025-03943-2 |
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