Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice
Abstract Optimizing intratumoral dendritic cell (DC)-T cell responses is pivotal for effective cancer immunotherapy. However, the mechanistic governing these dynamics within the tumor microenvironment (TME) remains unclear, and strategies to improve their therapeutic potential are underexplored. Her...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60769-3 |
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| author | Xiaozhe Yin Zexuan Ding Li Yu Xuhao Zhang Yu Gao Yiyan Li Zhibo Liu Yang-Xin Fu |
| author_facet | Xiaozhe Yin Zexuan Ding Li Yu Xuhao Zhang Yu Gao Yiyan Li Zhibo Liu Yang-Xin Fu |
| author_sort | Xiaozhe Yin |
| collection | DOAJ |
| description | Abstract Optimizing intratumoral dendritic cell (DC)-T cell responses is pivotal for effective cancer immunotherapy. However, the mechanistic governing these dynamics within the tumor microenvironment (TME) remains unclear, and strategies to improve their therapeutic potential are underexplored. Here, we show that precise radiotherapy activates the pro-TLR7/8 agonist imidazoquinoline (IMDQ) locally in preclinical tumor models, stimulating DCs to elicit T cell immunity without the need for further recruitment or causing systemic toxicity. Mechanistically, this synergistic approach triggers type I interferon via STING and MyD88 signaling pathways, strengthening local immune responses. Importantly, we reveal that fractionated, low-dose radiotherapy can effectively optimize local DC-T cell dynamics to control the irradiated tumor, while also promoting abscopal effect. Thus, our findings underscore the critical role of harnessing intratumoral DCs to reinvigorate pre-existing T cell immunity and provide mechanistic insights into improving both local and distal tumor control, opening new avenues for advancing cancer immunotherapy. |
| format | Article |
| id | doaj-art-30996477d3e44678bb737ae782a2bb21 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-30996477d3e44678bb737ae782a2bb212025-08-20T03:03:37ZengNature PortfolioNature Communications2041-17232025-07-0116111310.1038/s41467-025-60769-3Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in miceXiaozhe Yin0Zexuan Ding1Li Yu2Xuhao Zhang3Yu Gao4Yiyan Li5Zhibo Liu6Yang-Xin Fu7Department of Basic Medical Sciences, School of Medicine, Tsinghua UniversityChangping LaboratoryDepartment of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of Basic Medical Sciences, School of Medicine, Tsinghua UniversityBeijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking UniversityChangping LaboratoryDepartment of Basic Medical Sciences, School of Medicine, Tsinghua UniversityAbstract Optimizing intratumoral dendritic cell (DC)-T cell responses is pivotal for effective cancer immunotherapy. However, the mechanistic governing these dynamics within the tumor microenvironment (TME) remains unclear, and strategies to improve their therapeutic potential are underexplored. Here, we show that precise radiotherapy activates the pro-TLR7/8 agonist imidazoquinoline (IMDQ) locally in preclinical tumor models, stimulating DCs to elicit T cell immunity without the need for further recruitment or causing systemic toxicity. Mechanistically, this synergistic approach triggers type I interferon via STING and MyD88 signaling pathways, strengthening local immune responses. Importantly, we reveal that fractionated, low-dose radiotherapy can effectively optimize local DC-T cell dynamics to control the irradiated tumor, while also promoting abscopal effect. Thus, our findings underscore the critical role of harnessing intratumoral DCs to reinvigorate pre-existing T cell immunity and provide mechanistic insights into improving both local and distal tumor control, opening new avenues for advancing cancer immunotherapy.https://doi.org/10.1038/s41467-025-60769-3 |
| spellingShingle | Xiaozhe Yin Zexuan Ding Li Yu Xuhao Zhang Yu Gao Yiyan Li Zhibo Liu Yang-Xin Fu Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice Nature Communications |
| title | Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice |
| title_full | Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice |
| title_fullStr | Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice |
| title_full_unstemmed | Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice |
| title_short | Orchestrating intratumoral DC-T cell immunity for enhanced tumor control via radiotherapy-activated TLR7/8 prodrugs in mice |
| title_sort | orchestrating intratumoral dc t cell immunity for enhanced tumor control via radiotherapy activated tlr7 8 prodrugs in mice |
| url | https://doi.org/10.1038/s41467-025-60769-3 |
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