Authors
Emery Di Cicco, Caterina Miro, Annarita Nappi, Lucia Acampora, Jovan Isma, Stefano Sol, Serena Sagliocchi, Annunziata Gaetana Cicatiello, Federica Restolfer, Jessica Ferraro, Melania Murolo, Fabiana Boncimino, Michelle Liu, Yanek Jiménez-Andrade, Vincenza Cerbone, Claudia La Rocca, Victor A Neel, Giuseppe Matarese, Anna Mandinova, Mariano Stornaiuolo, Monica Dentice
Published in
Cell reports. Volume 45. Issue 7. Pages 117674. Jul 08, 2026. Epub Jul 08, 2026.
Abstract
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.
PMID:
42424140
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.
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