Anaplastic thyroid cancer: genomic landscape, molecular drivers and novel therapeutics

Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, defined by rapid progression, early metastasis and resistance to nearly all standard therapies. Although it accounts for less than 2% of thyroid cancers, ATC causes a disproportionate number of thyroid cancer-related deaths, with median overall survival rarely exceeding 10 months. Most patients present with unresectable or metastatic disease, leaving few curative options. The biology of ATC reflects a convergence of diverse oncogenic drivers and profound tumour plasticity. Frequent alterations in MAPK and PI3K pathways, loss of tumour suppressors and epigenetic deregulation fuel uncontrolled proliferation. A hypoxic and inflammatory microenvironment further promotes angiogenesis, immune evasion and metastatic spread. ATC cells also undergo extensive metabolic rewiring, shifting between glycolysis and oxidative phosphorylation to withstand nutrient and therapeutic stress. In parallel, stromal components, including fibroblasts, immune cells and endothelial networks, reinforce invasion and treatment resistance. In this Review, we highlight advances in the understanding of ATC biology, with a focus on driver genetic alterations, metabolic plasticity and microenvironmental interactions that underpin its exceptional aggressiveness. We also discuss how these biological insights provide a rationale for the design of multimodal therapeutic strategies urgently needed to improve outcomes for patients with ATC.