The shifting paradigm of programmed cell death ligand 1 (PD-L1) in anaplastic thyroid carcinoma: from pathology to clinical practice

Anaplastic thyroid carcinoma (ATC) represents one of the most aggressive human malignancies, characterized by rapid progression, early metastasis, and dismal prognosis. The emergence of immune checkpoint blockade targeting the PD-1/PD-L1 axis has revolutionized the therapeutic landscape for several cancers, including ATC, where traditional treatments have shown limited efficacy. This review provide a comprehensive overview of the biological, pathological, and clinical significance of PD-L1 in ATC, highlighting its diagnostic, prognostic, and therapeutic implications. A review of the literature was performed, encompassing molecular studies, immunohistochemical analyses, and clinical trials evaluating PD-L1 expression, its molecular correlates, and its predictive value for immunotherapy response in ATC. PD-L1 is expressed in a substantial proportion of ATCs, with positivity rates ranging from 20% to over 80% depending on the antibody clone, scoring method, and positivity threshold. Its expression correlates with oncogenic drivers such as BRAFV600E and TP53 mutations, and with an inflamed tumor microenvironment rich in CD8⁺ T cells and interferon-γ signatures. Although the prognostic value of PD-L1 remains controversial, its predictive value for immune checkpoint inhibitor (ICI) response is well established. Prospective trials demonstrated that only PD-L1–positive ATCs respond to single-agent ICI therapy, while combination regimens with kinase inhibitors yield benefit even in PD-L1–low tumors. PD-L1 expression defines a biologically and clinically relevant subset of ATCs with distinct immune features and therapeutic vulnerabilities. Standardizing PD-L1 testing and integrating it with molecular and microenvironmental biomarkers will be essential to refine patient selection for immunotherapy and combination strategies, improving outcomes.