The role of deiodinases on metabolic alteration in cancer

Deiodinases are key regulators of Thyroid Hormone (TH) bioavailability, exerting a precise spatial and temporal control over T3 levels in peripheral tissues. By dynamically modulating TH activation and inactivation, deiodinases allow target organs to adapt TH signaling to physiological and pathological demands, highlighting their importance in both health and disease. In cancer, their dysregulated expression reprograms cellular metabolism and shapes the tumor microenvironment (TME). Type 3 deiodinase (D3), frequently upregulated in proliferative and hypoxic tumor regions, fosters cell proliferation and resistance to differentiation. Conversely, type 2 deiodinase (D2) sustains glycolytic metabolism, angiogenesis, and redox disbalance, particularly in aggressive and p53-deficient tumors. Beyond cancer cells, deiodinases activity influences stromal and immune compartments, impacting glutamine metabolism and immune cell plasticity. This complex endocrine-metabolic axis supports tumor adaptation to stress and contributes to the emergence of resistance to therapy. Recent advances reveal the potential of targeting deiodinases to counteract cancer metabolic reprogramming and re-sensitize tumors to treatment. Given the essential and multifaceted roles of deiodinases in cancer biology, a comprehensive understanding of their mechanisms of action, regulation, and clinical implications is critical. This review aims to summarize current knowledge on the roles of deiodinases in cancer metabolism and immunity, focusing on their biochemical properties, regulatory networks, tissue-specific functions, and contributions to disease. In doing so, we seek to highlight emerging concepts in local TH signaling and explore potential avenues for therapeutic intervention targeting deiodinase pathways in precision oncology.