Thyroid hormone activation drives fibroblast identity and tumor remodeling in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma is a major cause of cancer-related mortality. Although immune checkpoint blockade improves outcomes, many patients fail to respond or develop resistance. Cancer-associated fibroblasts (CAFs) promote tumor progression and therapy resistance, but the signals that drive fibroblast reprogramming remain incompletely defined. Here, we show that thyroid hormone signaling, mediated by type 2 deiodinase (D2), regulates CAF activation. Single-cell transcriptomics and spatial RNA profiling identify a D2-positive fibroblast subpopulation that overlaps with immunomodulatory and matrix CAF states. RNA-seq analysis indicates that D2 supports activated and metabolically competent CAF programs. In vivo fibroblast-specific D2 deletion reduces CAF activation and limits tumor expansion. Spatial metabolomics further links D2-positive regions to metabolic remodeling of the tumor microenvironment and collagen-rich matrix deposition associated with aggressive tumor behavior. These findings support a role for D2-mediated thyroid hormone signaling in fibroblast reprogramming and suggest a therapeutic opportunity in cutaneous squamous cell carcinoma.