Current landscape of hypoxia in thyroid cancer pathogenesis and treatment

Thyroid cancer, the most prevalent endocrine malignancy, exhibits diverse clinical behaviors ranging from indolent to highly aggressive forms. A critical factor influencing the progression and treatment resistance of thyroid cancer is hypoxia-a condition characterized by inadequate oxygen supply to the tumor microenvironment. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α, drive various oncogenic processes such as epithelial-mesenchymal transition (EMT), angiogenesis, metabolic reprogramming, and immune evasion. These processes contribute to the aggressive phenotypes observed in poorly differentiated and anaplastic thyroid cancers. This review explores the molecular mechanisms by which hypoxia and HIFs influence thyroid cancer pathogenesis, focusing on key signaling pathways, including NF-κB, Wnt/β-catenin, Hedgehog, and others. Furthermore, we discuss potential therapeutic strategies targeting the hypoxic microenvironment, such as HIF inhibitors and natural compounds, which have shown promise in preclinical studies. Understanding the role of hypoxia in thyroid cancer not only offers insights into the disease's progression but also highlights new avenues for therapeutic intervention aimed at improving patient outcomes.