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

Background: 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. Methods: 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. Results: D2 was found to be highly expressed in CAFs, particularly iCAFs, exceeding levels observed in cancer epithelial cells. In vivo 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. Conclusions: 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.