EpCAM ⁺ Extracellular Vesicle PD‐L1 Dynamics as a Predictive Biomarker of Immune Checkpoint Blockade Response

Programmed death‐ligand 1 (PD‐L1) blockade improves outcomes in patients with various malignancies; however, biomarkers for monitoring treatment responses are lacking. This study presents a surface‐enhanced Raman scattering (SERS)‐based platform for the ultrasensitive detection of PD‐L1 on circulating epithelial cell adhesion molecule‐positive (EpCAM + ) extracellular vesicles (EVs). The platform is validated using interferon‐gamma‐treated epithelial tumor cell line‐derived EVs. The platform is further applied to paired pre‐ and post‐treatment plasma samples from patients with non‐small‐cell lung cancer ( n = 140) and head and neck squamous cell carcinoma ( n = 73) receiving anti‐PD‐(L)1 immunotherapy. Dynamic changes in PD‐L1 expression on EV are shown to correlate with clinical outcomes. A post‐treatment decrease in PD‐L1 expression on EpCAM + EVs (EpCAM + EV PD‐L1) is associated with improved 5‐year progression‐free and overall survival. These results establish EpCAM + EV PD‐L1 as a dynamic, non‐invasive biomarker for monitoring immunotherapy responses and demonstrate the utility of SERS‐based profiling in predicting long‐term responses to immune checkpoint blockade.