Spatial Transcriptomics Reveals Transcriptomic and Immune Microenvironment Reprogramming during Thyroid Carcinoma Dedifferentiation

Anaplastic thyroid carcinoma (ATC) is one of the most lethal human malignancies, often evolving from differentiated thyroid carcinoma (DTC) through a poorly understood dedifferentiation process. To elucidate this transition, spatial transcriptomic sequencing (spRNAseq) is performed on seven samples containing coexisting regions of ATC, poorly differentiated thyroid carcinoma, and DTC. SpRNAseq revealed that ATC regions were characterized by upregulated genes involved in immune suppression, angiogenesis, and extracellular matrix remodeling. Whole-exome sequencing and inferCNV analysis confirmed that adjacent DTC regions harbored mutational burdens comparable to those of ATC regions, suggesting early genomic priming for dedifferentiation. Trajectory analysis delineated a stepwise reprogramming process and identified four gene modules associated with the loss of thyroid differentiation, among which PDCD4 and TYMP emerged as key regulators. Notably, TYMP⁺ tumor-associated macrophages (TAMs) were highly enriched in ATC regions and contribute to an immunosuppressive microenvironment. Mechanistic experiments demonstrated that loss of PDCD4 led to eIF4A-dependent overexpression of immunosuppressive effectors, promoting the high infiltration of TYMP⁺TAMs in ATC. These findings support that coexisting DTC regions with ATC-like genomic alterations undergo sequential transcriptomic reprogramming and immune microenvironment remodeling to evolve into a full ATC pathological phenotype, in which PDCD4 loss-induced TAMs formation plays a critical role.