Circulating sEV PD-L1: A dual biomarker and therapeutic target in cancer immune evasion

Small extracellular vesicles (sEVs), especially those containing the programmed death ligand-1 (PD-L1) protein, have been identified as important players in the context of both the advancement of malignancy and resistance to treatments. The proteins, nucleic acids, and lipids contained in the sEVs released by malignancies promote the modulation of the tumor microenvironment, the induction of EMT, drug resistance, and the process of metastasis. Notably, sEV-PD-L1 extends the immunosuppressive role of membrane-bound PD-L1 by circulating systemically, thereby suppressing T cell activity beyond the primary tumor site. This review consolidates current knowledge on the biogenesis, secretion, and trafficking of sEVs, with a focus on the ESCRT machinery, Rab GTPases, and ceramide-dependent pathways. PD-L1 expression is governed by genomic alterations, microRNA regulation, post-transcriptional modifications, and oncogenic signaling that facilitate immune escape, while sEV-associated PD-L1 serves as a diagnostic and prognostic biomarker across multiple cancers and is detected using advanced isolation and sensing technologies. This review also highlights the therapeutic potential of sEVs as natural or engineered nanocarriers for chemotherapeutics, siRNAs, and immunomodulators, alongside strategies to block PD-L1–mediated immune suppression, while noting challenges in standardizing isolation, addressing tumor heterogeneity, and distinguishing sEV-associated PD-L1 from membrane-bound forms, thereby underscoring its dual role as a biomarker and therapeutic target in precision oncology.