Multiomics Profiling Reveals Distinct Immunosuppression and Metabolic Dysregulation in Aggressive Subtypes of Thyroid Cancer

Thyroid cancer comprises a heterogeneous group of malignancies with distinct clinical outcomes and molecular features, including papillary thyroid carcinoma (PTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC). This study aimed to delineate the molecular and immune landscapes of these subtypes and identify potential biomarkers for the aggressive forms, ATC and PDTC. We assembled a well-annotated cohort of 120 formalin-fixed paraffin-embedded samples, including 35 ATC, 18 PDTC, 37 PTC cases, and 30 adjacent normal tissues (N) paired with PTC, collected over the past decade from multiple hospitals. To our knowledge, this represents the largest clinical ATC/PDTC cohort subjected to multiomics profiling and the first comprehensive proteomic analysis of these aggressive thyroid cancers. Using 4D-data-independent acquisition proteomics on 118 tumors (ATC 34, PDTC 18, PTC 36, and N 30), integrated with total RNA-seq on 69 samples (ATC 10, PDTC 5, PTC 31, and N 23), we revealed substantial molecular similarities between ATC and PDTC, both markedly distinct from PTC and adjacent normal tissues. ATC and PDTC exhibited significant enrichment in immune-related and metabolic pathways, with transcriptomic data indicating aggressive phenotypes and pronounced immunosuppression. Distinct immune landscapes of ATC and PDTC were revealed with neutrophil extracellular trap formation and M0 macrophage accumulation as key immunosuppressive mechanisms. Notably, Fc fragment of IgG receptor IIa (CD32) was identified as a promising biomarker for ATC, implicating a functional link between immune evasion and tumor aggressiveness. Our findings provide a comprehensive molecular and immunological characterization of thyroid cancer subtypes, offering novel insights into the pathogenesis of ATC and PDTC, and identifying potential targets for diagnosis and precision therapy.