Epstein-Barr Virus-Associated HMGB1-Extracellular Vesicles Facilitate Macrophage PD-L1 Expression and Tumor Metastasis.

Abstract

Nasopharyngeal carcinoma (NPC) is a malignancy closely linked to Epstein-Barr virus (EBV) infection, and its progression is intricately associated with remodeling of the tumor microenvironment (TME). However, the role of EBV-associated extracellular vesicles (EVs), particularly those containing high mobility group box 1 (HMGB1), in NPC development remains poorly understood. This study utilized multiomics approaches to investigate the role of HMGB1-containing EVs (HMGB1-EVs) derived from EBV-associated NPC cells. Serum EVs from NPC patients were analyzed for HMGB1 content, and their diagnostic performance was evaluated. Mechanistic studies were performed to elucidate the regulation of HMGB1-EV biogenesis and their functional effects on immune cells within the TME. HMGB1-EVs exhibited high sensitivity and specificity for NPC diagnosis (AUC = 0.83), with significantly elevated HMGB1 levels detected in serum EVs from NPC patients. These levels were strongly associated with tumor stage, EBV-DNA load, and metastasis risk (AUC = 0.9), suggesting their potential as liquid biopsy biomarkers. Mechanistically, EBV infection induced Rab26 expression, facilitating the release of EV-associated HMGB1. In the TME, HMGB1-EVs were associated with an immunosuppressive macrophage phenotype by upregulating PD-L1 expression on macrophages via PLGRKT. This study reveals the molecular mechanism by which EBV-associated HMGB1-EVs may contribute to NPC progression and potential immune evasion. HMGB1-EVs hold promise as both diagnostic biomarkers and therapeutic targets, offering novel insights into the precision management of NPC.