Targeted alpha therapy for solid tumors: biological rationale, clinical advances, and future perspectives

Targeted alpha therapy (TAT) delivers high-linear-energy-transfer radiation over a few cell diameters and is being explored for resistant and microscopic solid-tumor disease. This targeted narrative review evaluates alpha-emitting platforms and clinical evidence by tumor type and development stage, with a focused literature update through 12 October 2026. Unlike broader radiochemistry-centered reviews, we place approved, randomized, early-phase, observational, and preclinical findings in separate evidence tiers. Radium-223 dichloride has randomized survival evidence in symptomatic bone-metastatic castration-resistant prostate cancer, whereas molecularly targeted actinium-225, lead-212, astatine-211, and thorium-227 agents remain investigational in the indications discussed. Updated examples include the 2026 ACTION-1 actinium-225-DOTATATE dosimetry substudy, the 2026 first-in-human astatine-211-MABG study, 2025 lead-212-DOTAMTATE phase II disclosures, and a negative 2025 mesothelin-targeted thorium-227 study. Quantitative outcomes are reported with their study design and limitations rather than interpreted as indirect head-to-head comparisons. Major barriers include isotope supply, incomplete daughter retention, salivary, marrow, and kidney toxicity, spatially heterogeneous target uptake, and uncertainty in patient-specific microdosimetry. We propose practical, imaging-led selection and a priority-ranked translational roadmap.