Single atom engineering for radiotherapy-activated immune agonist prodrugs
Abstract Immunotherapy has revolutionized cancer treatment by leveraging the body’s immune system to combat malignancies. However, on-target, off-tumour (OTOT) toxicity poses significant challenges, often leading to the failure of clinical trials for the development of immunotherapeutic drugs. The m...
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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/s41467-025-60768-4 |
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| _version_ | 1849238399523749888 |
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| author | Zexuan Ding Xiaozhe Yin Yuedan Zheng Yiyan Li Huanhuan Ge Jianshu Feng Ziyang Wang Simiao Qiao Qi Sun Fashuo Yu Zhanshan Hou Yang-Xin Fu Zhibo Liu |
| author_facet | Zexuan Ding Xiaozhe Yin Yuedan Zheng Yiyan Li Huanhuan Ge Jianshu Feng Ziyang Wang Simiao Qiao Qi Sun Fashuo Yu Zhanshan Hou Yang-Xin Fu Zhibo Liu |
| author_sort | Zexuan Ding |
| collection | DOAJ |
| description | Abstract Immunotherapy has revolutionized cancer treatment by leveraging the body’s immune system to combat malignancies. However, on-target, off-tumour (OTOT) toxicity poses significant challenges, often leading to the failure of clinical trials for the development of immunotherapeutic drugs. The molecular engineering of clinically relevant, tumour-selective prodrugs, activated in a targeted way, could help minimize systemic toxicity while maximizing anti-tumour efficacy. Here, we propose a Single Atom Engineering for Radiotherapy-Activated Prodrug (SAE-RAP) technique for the development of radiotherapy-activatable small-molecule immune agonist prodrugs. We show that introducing a single oxygen atom into the TLR7/8 agonist R848 significantly reduces the EC50 value by over 4000-fold, hence mitigating severe side effects following systemic administration. In preclinical tumour mouse models, exposure to radiotherapy removes the protective mask provided by the oxygen atom and locally rescues the activity of the prodrugs, triggering anti-tumour immunity and limiting the growth of primary and distal tumours. The SAE-RAP technique may be further utilized for developing radiotherapy-activated prodrugs for next-generation combination therapies that transcend traditional limitations. |
| format | Article |
| id | doaj-art-ac3be6c7d4bc45efa87f8b75670e6a11 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ac3be6c7d4bc45efa87f8b75670e6a112025-08-20T04:01:36ZengNature PortfolioNature Communications2041-17232025-07-0116111410.1038/s41467-025-60768-4Single atom engineering for radiotherapy-activated immune agonist prodrugsZexuan Ding0Xiaozhe Yin1Yuedan Zheng2Yiyan Li3Huanhuan Ge4Jianshu Feng5Ziyang Wang6Simiao Qiao7Qi Sun8Fashuo Yu9Zhanshan Hou10Yang-Xin Fu11Zhibo Liu12Changping LaboratoryDepartment 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 UniversityPeking University-Tsinghua University Centre for Life Sciences, Peking UniversityChangping LaboratoryChangping LaboratoryBeijing 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 LaboratoryPeking University-Tsinghua University Centre for Life Sciences, Peking UniversityChangping LaboratoryChangping LaboratoryChangping LaboratoryChangping LaboratoryAbstract Immunotherapy has revolutionized cancer treatment by leveraging the body’s immune system to combat malignancies. However, on-target, off-tumour (OTOT) toxicity poses significant challenges, often leading to the failure of clinical trials for the development of immunotherapeutic drugs. The molecular engineering of clinically relevant, tumour-selective prodrugs, activated in a targeted way, could help minimize systemic toxicity while maximizing anti-tumour efficacy. Here, we propose a Single Atom Engineering for Radiotherapy-Activated Prodrug (SAE-RAP) technique for the development of radiotherapy-activatable small-molecule immune agonist prodrugs. We show that introducing a single oxygen atom into the TLR7/8 agonist R848 significantly reduces the EC50 value by over 4000-fold, hence mitigating severe side effects following systemic administration. In preclinical tumour mouse models, exposure to radiotherapy removes the protective mask provided by the oxygen atom and locally rescues the activity of the prodrugs, triggering anti-tumour immunity and limiting the growth of primary and distal tumours. The SAE-RAP technique may be further utilized for developing radiotherapy-activated prodrugs for next-generation combination therapies that transcend traditional limitations.https://doi.org/10.1038/s41467-025-60768-4 |
| spellingShingle | Zexuan Ding Xiaozhe Yin Yuedan Zheng Yiyan Li Huanhuan Ge Jianshu Feng Ziyang Wang Simiao Qiao Qi Sun Fashuo Yu Zhanshan Hou Yang-Xin Fu Zhibo Liu Single atom engineering for radiotherapy-activated immune agonist prodrugs Nature Communications |
| title | Single atom engineering for radiotherapy-activated immune agonist prodrugs |
| title_full | Single atom engineering for radiotherapy-activated immune agonist prodrugs |
| title_fullStr | Single atom engineering for radiotherapy-activated immune agonist prodrugs |
| title_full_unstemmed | Single atom engineering for radiotherapy-activated immune agonist prodrugs |
| title_short | Single atom engineering for radiotherapy-activated immune agonist prodrugs |
| title_sort | single atom engineering for radiotherapy activated immune agonist prodrugs |
| url | https://doi.org/10.1038/s41467-025-60768-4 |
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