Targeting the Warburg Effect in Anaplastic Thyroid Carcinoma: Metabolic Vulnerabilities and Therapeutic Opportunities.

Abstract

Anaplastic thyroid carcinoma (ATC) represents the most aggressive thyroid malignancy, characterized by rapid progression, therapeutic resistance, and poor prognosis. Conventional treatments remain largely ineffective, highlighting the need for novel therapies. Metabolic reprogramming, particularly the Warburg effect (WE), has emerged as a promising area of investigation. This review synthesizes current evidence on the role of WE in ATC and PDTC, integrating data from molecular profiling, preclinical studies, and emerging therapeutic strategies. Oncogenic alterations frequently observed in ATC, including mutations in BRAF, RAS, TP53, and activation of PI3K/AKT/mTOR and HIF-1α signaling, converge to promote glycolytic reprogramming. This metabolic shift supports tumor proliferation, immune evasion, and metastasis through increased glucose uptake, lactate production, and microenvironmental remodeling. Key metabolic nodes, including glucose transporters, hexokinase, and monocarboxylate transporters, are regarded as promising targets. Preclinical studies suggest that pharmacological inhibition of these pathways reduces tumor growth, enhances radiosensitivity, and improves response to targeted therapies. Future efforts should focus on combination therapies, biomarker-driven patient stratification, and the development of targeted delivery systems to overcome toxicity and resistance. A deeper understanding of tumor metabolic heterogeneity will be essential for translating these approaches into clinical practice.