Type 2 Deiodinase in Cancer-Associated Fibroblasts is required to sustain growth of poorly and undifferentiated thyroid cancer

Poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) are characterized by rapid progression and poor patient survival. While the tumor microenvironment (TME) - particularly cancer-associated fibroblasts (CAFs)- plays a crucial role in supporting tumor growth, its metabolic contribution remains poorly understood. Here, we identify a critical role for type 2 deiodinase (D2), the enzyme that activates the thyroid hormone (TH) thyroxine (T4) into the biologically active triiodothyronine (T3), in sustaining a pro-tumorigenic TME in PDTC and ATC. We show that D2 is expressed not only in thyroid epithelial cancer cells, but at even higher levels in CAFs, especially inflammatory CAFs (iCAFs). In in vivo mouse models, pharmacological inhibition of D2 reduces tumor growth and alters composition of CAFs. In 3D co-culture spheroids, D2 activity proves essential for supporting tumor cell proliferation by establishing a paracrine loop between stromal and epithelial cancer cells that amplifies local TH signaling. Notably, human PDTC organoids expressing D2 respond to modulation of TH levels, confirming the functional relevance of this metabolic axis in human tumors. In conclusion, these findings identify D2 as a key mediator of stromal-epithelial crosstalk in PDTC and ATC, and highlight local TH metabolism as a potential therapeutic target in these lethal cancers.