Abstract

Objective: To review the major tissue-based and circulating forms of programmed death-ligand 1 (PD-L1) from a diagnostic pathology perspective. Methods: This article is a targeted narrative review based on a selective synthesis of literature retrieved from PubMed, Scopus, and Google Scholar, updated to April 2026. Key search terms included “PD-L1”, “PD- L1 immunohistochemistry”, “soluble PD-L1”, “exosomal PD-L1”, “PD-L1 glycosylation”, “nuclear PD-L1”, “liquid biopsy”, “spatial pathology”, “artificial intelligence”, “machine learning”, and “immune checkpoint inhibitor”. Results: PD-L1 is a multilayered biomarker that exists as membranous, glycosylated, nuclear, soluble, exosomal/extracellular vesicle-associated, circulating tumor cell-associated, and circulating RNA forms. Membranous PD-L1 assessed by tissue immunohistochemistry remains the current clinical foundation, but interpretation depends on specimen type, antibody clone, testing platform, cutoff value, tumor heterogeneity, and pre-analytical variables. Non-IHC PD-L1 assays provide additional biological and translational information but are not yet sufficiently standardized to replace routine practice. Conclusion: A multilayered view of PD-L1 may help pathologists interpret PD-L1 results more accurately, avoid overinterpretation, and better support personalized immunotherapy.