DAMPs and NETs in Thyroid Diseases: Biological, Diagnostic, and Translational Perspectives

Thyroid diseases encompass a broad spectrum of autoimmune, inflammatory, and neoplastic disorders, yet current diagnostic approaches provide limited insight into innate immune activation and tumor-associated inflammatory remodeling. Damage-associated molecular patterns (DAMPs) and neutrophil extracellular traps (NETs) have emerged as interconnected mediators of sterile inflammation with potential relevance to thyroid carcinogenesis, disease progression, and biomarker development. This narrative review synthesized literature identified through PubMed/MEDLINE and Scopus to evaluate the biological, diagnostic, and translational significance of DAMP- and NET-associated pathways in thyroid diseases, with particular emphasis on thyroid cancer. DAMPs such as high-mobility group box 1 (HMGB1), S100A8/A9, serum amyloid A, heat shock proteins, and extracellular nucleic acids may sustain inflammatory signaling through pattern-recognition receptors and contribute to tumor proliferation, angiogenesis, immune modulation, and therapeutic resistance. In parallel, circulating analytes associated with NET biology—including nonspecific cell-free DNA (cfDNA) and nucleosomes, pathway-associated citrullinated histone H3 (CitH3), and composite myeloperoxidase–DNA (MPO–DNA) complexes—have shown associations with thyroid malignancy, dedifferentiated disease, metastatic presentation, and greater disease severity. Experimental data further suggest that aggressive thyroid cancer cells, particularly anaplastic thyroid carcinoma, can induce extracellular trap formation and exploit neutrophil-derived signals to support tumor growth. However, limited disease specificity, assay heterogeneity, and the predominance of small or exploratory cohorts currently restrict clinical implementation. Future strategies should prioritize standardized, prospective validation of multimarker panels integrating DAMP- and NET-related analytes with imaging, cytology, molecular diagnostics, and clinicopathological risk stratification to determine whether they provide incremental value for diagnosis, prognostication, and longitudinal monitoring in thyroid cancer.