Thyroid dedifferentiation is one of the defining features of advanced thyroid cancers and is associated with aggressive behaviour, therapeutic resistance, and an immunosuppressive tumour ecosystem. However, how dedifferentiation remodels this ecosystem remains poorly understood. We investigated this process using loss of FOXE1, a thyroid lineage transcription factor progressively lost during dedifferentiation, as an experimental model.
Tamoxifen-inducible Foxe1 knockout mice1 were used to model thyroid dedifferentiation in vivo. Mice developed biochemical hypothyroidism accompanied by prominent myeloid cell infiltration, particularly macrophages and mast cells. Bulk RNA sequencing and NanoString GeoMx spatial transcriptomics were performed on thyroid tissue from tamoxifen- and vehicle-treated mice (n=3 per group) to identify immunomodulatory pathways. TCGA2 bulk RNA-seq data from 391 papillary thyroid carcinomas (PTCs) were analysed to assess the relationship between FOXE1-repressed genes and the Thyroid Differentiation Score (TDS). Single-cell RNA sequencing was performed on 10 PTCs collected at Royal North Shore Hospital and integrated with publicly available datasets.
Spatial transcriptomics of FOXE1-deficient thyroids identified marked induction of cytokines and immune-regulatory genes, including ECRG4, GDF15, and TGFBI (all fold change >2, adjusted P<0.01). These FOXE1-repressed genes were inversely correlated with tumour differentiation in TCGA. Human PTCs similarly demonstrated increased expression of immunomodulatory cytokines in FOXE1-low tumour epithelial cells.
These findings demonstrate that thyroid dedifferentiation actively remodels the immune landscape through altered cytokine signalling and myeloid cell interactions. Together, they identify a mechanism linking loss of thyroid lineage identity to immune remodelling and highlight candidate therapeutic targets for aggressive, immunotherapy-resistant thyroid cancers.