Spatiotemporal Imaging Dynamics and Divergent Immune Mechanisms of ²¹¹At- Versus ¹³¹I‑Induced Thyroid Injury

Targeted alpha therapy (TAT) with Astatine-211 (²¹¹At) has shown potent antitumor efficacy, yet free ²¹¹At released through deastatination accumulates in the thyroid via the sodium-iodide symporter (NIS), posing safety concerns distinct from β-emitter counterparts such as ¹³¹I. Here, we combine multimodal in vivo imaging and molecular profiling to resolve the kinetics-toxicity relationship of ²¹¹At- versus ¹³¹I-induced thyroid injury. Using serial ^99mTcO₄ ^- SPECT/CT and ¹⁸F-FDG PET/CT, we captured the dynamic evolution of thyroid function and metabolic inflammation in BALB/c mice receiving equipotent cytotoxic doses of Na¹³¹I (18.5 MBq), low-dose Na²¹¹At (18.5 kBq), or high-dose Na²¹¹At (92.5 kBq). Biodistribution study revealed rapid NIS-mediated uptake of ²¹¹At peaking at 7 h and complete clearance by 44 h, yet subsequent SPECT and hormonal analyses demonstrated progressive thyroidal dysfunction independent of residual activity. PET-based metabolic imaging confirmed persistent inflammatory stress despite radionuclide clearance. By integrating multimodal spatiotemporal imaging, cytokine profiling, RNA sequencing, and immune deconvolution techniques, we identified fundamental distinctions between α and β irradiation in immunopathological mechanisms. While β irradiation predominantly elicited transient innate immune activation, high-LET α-particle exposure preferentially shifted the thyroid immune landscape toward an antigen-experienced adaptive state. This immune remodeling may contribute to the persistence of thyroidal dysfunction and inflammatory stress following α-particle exposure, even after radionuclide clearance. This spatiotemporal imaging framework provides a mechanistic basis for understanding α-induced organ injury, challenges dose-centric safety models, and guides the design and monitoring of future TAT regimens.