The IGF signaling axis in thyroid cancer: biological complexity and therapeutic challenges

Dysregulation of the insulin-like growth factor (IGF) axis plays an important role in thyroid cancer progression, dedifferentiation, and therapeutic resistance. While most differentiated thyroid cancers have favorable outcomes, a clinically significant subset develops aggressive behavior or becomes radioiodine (RAI) refractory, for which effective treatments remain limited. Aberrant activation of IGF ligands, IGF-1 receptor (IGF-1R), insulin receptor isoforms (especially IR-A), and IGF-binding proteins (IGFBPs) enhances oncogenic signaling through the PI3K/AKT and MAPK pathways and disrupts differentiation programs essential for iodine handling. Emerging evidence supports an IGF-2/IR-A-dominant autocrine circuit as a feature of aggressive and RAI-refractory disease, highlighting its potential relevance for biomarker-driven patient stratification. However, the clinical translation of IGF-axis targeting in thyroid cancer remains limited, and IGF-1R-directed monotherapies have shown only modest efficacy owing to signaling redundancy, adaptive resistance, metabolic toxicities, and the lack of validated predictive biomarkers for patient selection. Consequently, current translational efforts increasingly emphasize rational combination strategies, targeted delivery platforms, and molecular imaging approaches. This review summarizes key mechanistic and translational insights into IGF signaling in thyroid cancer and discusses how IGF-axis modulation may be integrated into precision oncology strategies for advanced disease.