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

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.