Abstract:Differentiated thyroid carcinoma (DTC) generally carries a favorable prognosis; however, its malignant progression and resistance to radioactive iodine therapy are strongly associated with specific driver gene mutations. Alterations in key genes-such as BRAF, RAS, TERT, and RET-not only influence tumor differentiation, aggressiveness, and recurrence risk but also provide critical molecular information for risk stratification, prognostic evaluation, and individualized therapeutic decision-making. With the increasing availability of multi-gene testing, the diagnostic accuracy for cytologically indeterminate thyroid nodules has markedly improved, and gene profiling has become essential in guiding neoadjuvant strategies for locally advanced disease. Targeted therapies, including multi-kinase inhibitors and gene-specific inhibitors (e.g., BRAF and RET inhibitors), have significantly improved survival outcomes in patients with radioactive iodine-refractory DTC. Nevertheless, acquired resistance and treatment-related adverse events remain major limitations. Emerging evidence suggests that dual-target inhibition and combinations of targeted therapy with immunotherapy may yield additional clinical benefits. This review summarizes the clinical implications of major gene mutations in DTC, the application of multi-gene testing, and recent advances in targeted therapies to support precision management.