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<p>Targeted alpha therapy (TAT) has emerged as a promising radiopharmaceutical modality in precision oncology. Compared to beta-emitters, alpha-emitters exhibit superior properties, including higher linear energy transfer, shorter penetration range, enhanced resistance to hypoxic conditions, and convenient radiation protection. Notably, alpha-emitters also demonstrate therapeutic efficacy against a subset of tumors exhibiting resistance to beta-radiotherapy. In 2013, the first α-particle therapeutic agent, ²²³RaCl₂ (Xofigo<sup>®</sup>), was approved by the FDA for treating bone metastases in advanced castration-resistant prostate cancer, marking a milestone in clinical translation of alpha-emitters. However, the biological mechanisms underlying alpha-particle-mediated therapeutic effects remain incompletely elucidated, which has hindered the optimization of precision treatment strategies. This review systematically analyzes TAT’s tripartite antitumor mechanisms—targeted effects, bystander effects and abscopal effects—thereby constructing a “local-regional-systemic” multidimensional antitumor network. This framework not only clarifies the radiobiological principles of α-emitters but also provides innovative perspectives for advancing TAT applications in tumor precision therapy.</p> Graphical abstract <p></p>

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Targeted alpha therapy: a comprehensive analysis of the biological effects from “local-regional-systemic” dimensions

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月11日

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  • Zhiling Song,
  • Jiajia Zhang,
  • Shanshan Qin,
  • Xiaohui Luan,
  • Han Zhang,
  • Mengdie Yang,
  • Yao Jin,
  • Gang Yang,
  • Fei Yu

摘要

Targeted alpha therapy (TAT) has emerged as a promising radiopharmaceutical modality in precision oncology. Compared to beta-emitters, alpha-emitters exhibit superior properties, including higher linear energy transfer, shorter penetration range, enhanced resistance to hypoxic conditions, and convenient radiation protection. Notably, alpha-emitters also demonstrate therapeutic efficacy against a subset of tumors exhibiting resistance to beta-radiotherapy. In 2013, the first α-particle therapeutic agent, ²²³RaCl₂ (Xofigo®), was approved by the FDA for treating bone metastases in advanced castration-resistant prostate cancer, marking a milestone in clinical translation of alpha-emitters. However, the biological mechanisms underlying alpha-particle-mediated therapeutic effects remain incompletely elucidated, which has hindered the optimization of precision treatment strategies. This review systematically analyzes TAT’s tripartite antitumor mechanisms—targeted effects, bystander effects and abscopal effects—thereby constructing a “local-regional-systemic” multidimensional antitumor network. This framework not only clarifies the radiobiological principles of α-emitters but also provides innovative perspectives for advancing TAT applications in tumor precision therapy.

Graphical abstract