The article discusses a study evaluating CD46-targeted alpha particle therapy using Actinium-225 ([225Ac]Macropa-PEG4-YS5) for treating metastatic castration-resistant prostate cancer (mCRPC), particularly in cases where tumors lack prostate-specific membrane antigen (PSMA) expression. Researchers utilized a CD46-targeting PET imaging agent, [89Zr]DFO-YS5, to detect microtumor lesions in organs like the liver, kidneys, and lungs. The therapy demonstrated high radiation dose deposition in small tumors, leading to effective tumor ablation and improved survival in early-stage lesions. However, in larger tumors, heterogeneous dose distribution reduced efficacy, necessitating higher administered activity for a complete response. These findings suggest that [225Ac]Macropa-PEG4-YS5 holds potential for clinical translation in treating metastatic prostate cancer and highlight the importance of microdosimetry in understanding and optimizing targeted alpha therapy.