Thyroid hormone inactivation sustains cancer stem cell maintenance and tumorigenesis in basal cell carcinoma

: A hierarchical organization within a tumor underlies the varying capacities of cancer cells to proliferate, metastasize, and drive relapse. Cancer stem cells (CSCs) are resistant to conventional therapies, making them critical targets for cancer treatment. Thyroid hormone (TH), a key regulator of proliferation and differentiation, is tightly controlled by the deiodinase enzymes. By integrating in vivo animal studies in a genetic mouse model of basal cell carcinoma (BCC) with analyses of human BCC specimens, we demonstrate that deiodinase type 3 (D3), the TH-inactivating enzyme, is expressed in the most tumorigenic CSC subpopulation. D3 genetic ablation significantly reduces the CSC population within protumorigenic niches and downregulates key stemness markers, including the transcription factor Sox9. Similarly, systemic induction of hyperthyroidism leads to a reduction of the CSC pool. Importantly, analysis of human BCC specimens revealed that D3 is highly enriched in the CSC niche. Mechanistically, we found that TH treatment suppresses Sox9 expression. These findings demonstrate that D3 sustains the tumorigenic potential of BCC CSCs by protecting them from TH-induced apoptosis and differentiation. Targeting the D3/TH axis may represent a promising therapeutic strategy to reduce the ability to self-renew of CSCs and inhibit tumor progression in BCC.