2. Academic Validation
  3. High-risk EBV promotes immune evasion in nasopharyngeal carcinoma by upregulating HLA-DP via the encoded BALF2-HR variant

High-risk EBV promotes immune evasion in nasopharyngeal carcinoma by upregulating HLA-DP via the encoded BALF2-HR variant

  • Nat Commun. 2026 Mar 27. doi: 10.1038/s41467-026-70725-4.
Yi Meng # 1 2,  Qian Wang # 1 2,  Lei Shi # 3,  Qijia Yan 2 4,  Qianqian He 1 2,  Pinglang Ruan 1 2,  Ziwei Chen 1 2,  Dan Wang 2,  Hongke Qu 2,  Pan Chen 1 2,  Zhaojian Gong 3,  Fuyan Wang 1 2,  Bo Xiang 1 2 5,  Ming Zhou 1 2,  Ming Tan 2 6,  Guiyuan Li 1 2,  Can Guo 1 2 5,  Zhaoyang Zeng 7 8,  Junshang Ge 9 10 11,  Wei Xiong 12 13 14
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
  • 2 Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
  • 3 Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5 Furong Laboratory, Changsha, Hunan, China.
  • 6 Institute of Biochemistry & Molecular Biology, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
  • 7 NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. [email protected].
  • 8 Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China. [email protected].
  • 9 NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. [email protected].
  • 10 Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China. [email protected].
  • 11 Furong Laboratory, Changsha, Hunan, China. [email protected].
  • 12 NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. [email protected].
  • 13 Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China. [email protected].
  • 14 Furong Laboratory, Changsha, Hunan, China. [email protected].
  • # Contributed equally.
PMID: 41896559 DOI: 10.1038/s41467-026-70725-4
Abstract

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia, with genetic factors playing a significant role in its occurrence. The HLA gene region on chromosome 6 is linked to NPC susceptibility, but the mechanisms remain unclear. Epstein-Barr virus (EBV) Infection is a well-established cause, with 95% of NPC patients being EBV-positive. Three key variations in the EBV genome (162215_C, 162476_C, 163364_T) in the BALF2 gene are strongly associated with NPC risk. This study finds that the high-risk BALF2 variant (BALF2-HR) upregulates HLA class II molecules, such as HLA-DP, which interacts with LAG-3 on CD8⁺ T cells, inhibiting cytokine secretion and promoting T cell exhaustion, leading to immune evasion and reduced anti-PD-1 efficacy. BALF2-HR also enhances HLA-DP transcription by binding to KPNA2 and facilitating CIITA nuclear translocation. Conjunctive immunotherapy with anti-LAG-3 and anti-PD-1 antibodies significantly improves NPC treatment. This work introduces a new therapeutic strategy for NPC and insights into infection-associated cancers.

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