Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung
Abstract Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55751-4 |
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| author | Tianchuan Zhu Yuchen Xiao Zhenxing Chen Hanxi Ding Shoudeng Chen Guanmin Jiang Xi Huang |
| author_facet | Tianchuan Zhu Yuchen Xiao Zhenxing Chen Hanxi Ding Shoudeng Chen Guanmin Jiang Xi Huang |
| author_sort | Tianchuan Zhu |
| collection | DOAJ |
| description | Abstract Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@cGAMP) to remodel the tumor microenvironment and thereby enhance CAR-T cell activity. Following pulmonary delivery, the nanovesicles rapidly accumulate in the lung and selectively deliver STING agonists to PD-L1-overexpressing cells via the PD-1/PD-L1 interaction. This targeted delivery effectively avoids the systemic inflammation and poor cellular uptake that plague free STING agonists. Internalized STING agonists trigger STING signaling and induce interferon responses, which diminish immunosuppressive cell populations such as myeloid-derived suppressor cells in the tumor microenvironment and promote CAR-T cell infiltration. Importantly, the anti-PD-L1 single chain variable fragment on the nanovesicle surface blocks PD-L1 upregulation induced by STING agonists and prevents CAR-T cell exhaustion. In both orthotopic lung cancer and lung metastasis model, combined therapy with CAR-T cells and aPD-L1 NVs@cGAMP potently inhibits tumor growth and prevents recurrence. Therefore, aPD-L1 NVs@cGAMP is expected to serve as an effective CAR-T cell enhancer to improve the efficacy of CAR-T cells against solid tumors. |
| format | Article |
| id | doaj-art-e88c1aad4069495396e62f035fa6c37f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-e88c1aad4069495396e62f035fa6c37f2025-01-05T12:39:18ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-024-55751-4Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lungTianchuan Zhu0Yuchen Xiao1Zhenxing Chen2Hanxi Ding3Shoudeng Chen4Guanmin Jiang5Xi Huang6Center for Infection and Immunity, Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen UniversityCenter for Infection and Immunity, Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen UniversityCenter for Infection and Immunity, Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen UniversityCenter for Infection and Immunity, Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen UniversityGuangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen UniversityDepartment of Clinical laboratory, The Fifth Affiliated Hospital of Sun Yat-sen UniversityCenter for Infection and Immunity, Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen UniversityAbstract Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@cGAMP) to remodel the tumor microenvironment and thereby enhance CAR-T cell activity. Following pulmonary delivery, the nanovesicles rapidly accumulate in the lung and selectively deliver STING agonists to PD-L1-overexpressing cells via the PD-1/PD-L1 interaction. This targeted delivery effectively avoids the systemic inflammation and poor cellular uptake that plague free STING agonists. Internalized STING agonists trigger STING signaling and induce interferon responses, which diminish immunosuppressive cell populations such as myeloid-derived suppressor cells in the tumor microenvironment and promote CAR-T cell infiltration. Importantly, the anti-PD-L1 single chain variable fragment on the nanovesicle surface blocks PD-L1 upregulation induced by STING agonists and prevents CAR-T cell exhaustion. In both orthotopic lung cancer and lung metastasis model, combined therapy with CAR-T cells and aPD-L1 NVs@cGAMP potently inhibits tumor growth and prevents recurrence. Therefore, aPD-L1 NVs@cGAMP is expected to serve as an effective CAR-T cell enhancer to improve the efficacy of CAR-T cells against solid tumors.https://doi.org/10.1038/s41467-024-55751-4 |
| spellingShingle | Tianchuan Zhu Yuchen Xiao Zhenxing Chen Hanxi Ding Shoudeng Chen Guanmin Jiang Xi Huang Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung Nature Communications |
| title | Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung |
| title_full | Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung |
| title_fullStr | Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung |
| title_full_unstemmed | Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung |
| title_short | Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung |
| title_sort | inhalable nanovesicles loaded with a sting agonist enhance car t cell activity against solid tumors in the lung |
| url | https://doi.org/10.1038/s41467-024-55751-4 |
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