Single atom engineering for radiotherapy-activated immune agonist prodrugs

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 () and Zhibo Liu ()
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Zexuan Ding: Changping Laboratory
Xiaozhe Yin: Tsinghua University
Yuedan Zheng: Peking University
Yiyan Li: Peking University
Huanhuan Ge: Changping Laboratory
Jianshu Feng: Changping Laboratory
Ziyang Wang: Peking University
Simiao Qiao: Changping Laboratory
Qi Sun: Peking University
Fashuo Yu: Changping Laboratory
Zhanshan Hou: Changping Laboratory
Yang-Xin Fu: Changping Laboratory
Zhibo Liu: Changping Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60768-4

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