Epstein–Barr Virus‐Associated
HMGB1
‐Extracellular Vesicles Facilitate Macrophage
PD
‐
L1
Express
Shi‐Rui Du, Zong‐Chang Qin, Wen‐Tao Zhao, Tian‐Yi Lin, Yang‐Yang Du, Jia‐Cheng Qu, Jia Yan, Qian Zhong, Ning Meng ABSTRACT
Backgrounds
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.
Methods
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.
Results
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.
Conclusion
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.