Theranostic and Radionuclide-based Treatment Approaches for Radioiodine-refractory Thyroid Cancer: From Biology to Clinical Application.

When differentiated thyroid cancer stops taking up radioiodine, treatment becomes significantly more challenging, and the disease often behaves more aggressively. Systemic therapies such as multikinase inhibitors and mutation-specific drugs have expanded available options, but many patients experience side effects, and responses can vary widely. At the same time, advances in molecular imaging and targeted radionuclide therapy are changing how this condition is managed. Short-term MAPK inhibition can restore iodine uptake in some patients, creating an opportunity to give radioiodine again. For patients with spreading or fast-growing disease, a growing range of theranostic agents, including Lu and Ac-based treatments directed at SSTR, PSMA, or FAP, provides a more targeted approach that is guided by PET imaging and has shown promising activity in early clinical experience- The increasing use of quantitative PET information, radiomic analysis, and personalized dosimetry may further support better treatment selection. Despite these developments, the optimal combination of radionuclide therapy with redifferentiation strategies, multikinase inhibitors, and gene-targeted treatments remains unclear. This review brings together current and emerging treatment approaches for radioiodine-refractory thyroid cancer and discusses how theranostics may become part of routine care.