Determinants of redifferentiation response in radioiodine-refractory differentiated thyroid cancer: from lineage reversibility to therapeutic radioiodine delivery

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) arises when tumour evolution disrupts the coordinated thyroid-follicular program required for radioiodine (RAI) uptake, retention and therapeutic radiation delivery. Pharmacological inhibition of oncogenic MAPK signaling has established that this loss is reversible in a subset of tumors, yet restoration of RAI avidity remains heterogeneous and does not necessarily translate into tumor control. Rather than cataloguing redifferentiation agents, this Review asks where and why recovery succeeds or fails as tumors progress from molecular reprogramming to therapeutically meaningful RAI response. We conceptualize redifferentiation as a sequence of biologically distinct but interconnected transitions: thyroid-lineage reactivation, restoration of functional surface NIS, iodide uptake and retention, lesion-level radiation delivery and tumor response. Each transition introduces specific bottlenecks and candidate determinants. Clinical evidence indicates that genotype shapes, but does not uniquely determine, redifferentiation response, whereas markers of residual differentiation, chromatin state and metabolic phenotype remain incompletely validated. This transition-based framework distinguishes pretreatment prediction of lineage recovery from post-induction functional selection using iodine imaging and dosimetry, and explains why restored RAI avidity should be regarded as an intermediate functional phenotype rather than a therapeutic endpoint. MAPK-directed therapy currently provides the strongest clinical foundation for redifferentiation, whereas chromatin- and trafficking-directed approaches remain predominantly mechanistic or preclinical. Future studies should integrate baseline tumor state, dynamic lineage response, functional iodine handling, lesion-level radiation delivery and clinical outcome within the same prospective framework. Such integration may move redifferentiation beyond empirical restoration of iodine avidity toward mechanism-informed recovery of therapeutically meaningful thyroid function.