Thyroid Hormone Activation Drives Fibroblast Identity and Tumor Remodeling in Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is a major cause of cancer-related mortality, with Cancer-Associated Fibroblasts (CAFs) acting as central drivers of tumor progression and immunotherapy resistance. We identified Type 2 deiodinase (D2)-mediated thyroid hormone signaling as a critical regulator of CAF activation. To elucidate the molecular mechanisms governing this reprogramming, we performed RNA-sequencing on CAFs isolated from fibroblast-specific D2 knockout (Col1a2-Cre; D2fl/fl) and wild-type mice (Col1a2-Cre; D2wt/wt). Furthermore, we assessed transcriptional rescue by treating D2-deficient CAFs with exogenous T3. This dataset defines the D2-dependent gene signatures associated with metabolic remodeling and collagen-rich matrix deposition, identifying thyroid hormone signaling as a driver of fibroblast heterogeneity and a potential therapeutic vulnerability in cSCC.