Molecular pathogenesis and therapeutic advances in RET fusion-positive papillary thyroid carcinoma

Thyroid cancer represents the fastest-growing endocrine malignancy worldwide, with papillary thyroid carcinoma (PTC) being its predominant pathological subtype. RET fusion is a key driver genetic alteration in PTC, closely associated with enhanced tumor invasiveness and poorer prognosis in some cohorts. This review systematically summarizes the molecular pathogenesis of RET fusion-positive PTC, encompassing the structure and function of the RET proto-oncogene and its encoded protein, the molecular characteristics of fusion events (predominantly CCDC6-RET and NCOA4-RET), the mechanisms underlying sustained activation of classical signaling pathways, and the novel regulatory mechanism of liquid-liquid phase separation. Furthermore, the review elaborates on the clinical efficacy of highly selective RET inhibitors (selpercatinib and pralsetinib), including their breakthroughs in pediatric patients and radioactive iodine-refractory cases. Primary and acquired resistance mechanisms (on-target mutations, bypass activation) and corresponding strategies (next-generation inhibitors, combination therapies) are also analyzed. By integrating recent advances in basic and clinical research, this review provides a comprehensive reference for the precision diagnosis and treatment, mechanistic investigation, and drug development for RET fusion-positive PTC.