Transcriptome of Anaplastic Thyroid Cancer Reveals Two Molecular Subtypes with Distinct Tumor Microenvironment and Prognosis

<b><i>Background:</i></b> Although patients with anaplastic thyroid cancer (ATC) generally have a poor prognosis and there are currently no effective treatment options, survival and response to therapy vary between patients. Genomic and transcriptomic profiles of ATC have been reported; however, a comprehensive study of the tumor microenvironment (TME) of ATC is still lacking. This study aimed to elucidate the TME characteristics associated with ATC and their prognostic implications. <b><i>Methods:</i></b> We analyzed bulk RNA transcriptomic data from 1,634 samples-including 476 normal thyroid tissues, 25 benign thyroid adenomas, 340 <i>RAS</i>-like and 719 <i>BRAF</i>^V600E-like differentiated thyroid cancers (DTC-R and DTC-B, respectively), and 74 ATCs. We assessed the TME and molecular characteristics of these thyroid cancer subtypes using deconvolution analysis. <b><i>Results:</i></b> The TME of ATC was characterized by a high abundance of immune cells and fibroblasts and a low abundance of epithelial cells compared to other thyroid histologies. During its malignant evolution, ATC exhibited an ecotype more closely related to DTC-B than <i>RAS</i>-like DTC (DTC-R). Furthermore, we identified two distinct molecular subtypes within ATC with significant differences in their TMEs. We termed the subtype with increased immune cells and fibroblasts as ATC-immune-fibroblast (ATC-IF) and the subtype with elevated epithelial and endothelial cells as ATC-epithelial-endothelial (ATC-E). The ATC-IF group had worse disease-specific survival (log-rank <i>p</i> = 0.035), higher ERK scores, and lower thyroid differentiation scores than the ATC-E group. While both ATC subtypes had elevated immune cells and fibroblasts compared to DTC-R and DTC-B, this increase was more pronounced in ATC-IF, with a marked rise in myeloid lineage cells and promigratory fibroblasts. Immune checkpoint gene expression and epithelial-mesenchymal transition scores were significantly higher in the ATC-IF group than in the ATC-E group. <b><i>Conclusion:</i></b> ATC shows a TME distinct from that of DTC and can be further divided into two molecular subtypes-each with its own unique TME. The ATC-IF group, with a poorer prognosis and higher ERK score, is enriched in immune cells and fibroblasts, which may represent potential therapeutic targets.