Type 2 Deiodinase in Cancer-Associated Fibroblasts is Required to Sustain Growth of Poorly and Undifferentiated Thyroid Cancer

<b><i>Background:</i></b> Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are aggressive thyroid cancers with limited treatment options and poor prognosis. While the tumor microenvironment (TME), especially cancer-associated fibroblasts (CAFs), is known to support tumor growth, its metabolic role is not well understood. This study aimed to investigate the role of type 2 deiodinase (D2)-an enzyme converting thyroxine to active triiodothyronine (T3)-in sustaining a pro-tumorigenic TME in PDTC and ATC. <b><i>Methods:</i></b> We analyzed D2 expression in both thyroid cancer epithelial cells and CAFs, including inflammatory CAFs (iCAFs), using murine and human PDTC/ATC models. Functional relevance was assessed through pharmacological inhibition of D2 in mouse xenograft models and coculture three-dimensional (3D) spheroids. The effects on tumor growth, CAF composition, and epithelial-stromal signaling were evaluated. In addition, human PDTC-derived organoids were used to test responsiveness to thyroid hormone (TH) modulation. <b><i>Results:</i></b> D2 was found to be highly expressed in CAFs, particularly iCAFs, exceeding levels observed in cancer epithelial cells. <i>In vivo</i> inhibition of D2 led to reduced tumor growth and changes in CAF profiles and activation. In 3D coculture spheroids, D2 activity was essential for tumor cell proliferation via a paracrine loop that enhanced local TH signaling. Human PDTC organoids expressing D2 also responded to TH modulation, confirming a positive effect of T3 on tumoral growth in this context. <b><i>Conclusions:</i></b> We identified D2 as a key mediator of stromal-epithelial cross talk in PDTC and ATC and highlight local TH metabolism as a potential therapeutic target in these lethal cancers.