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

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. Susceptibility of Nasopharyngeal carcinoma (NPC), associated with Epstein-Barr virus infection, is linked with HLA gene region with mechanisms unclear. The authors here show that the high-risk EBV subtype BALF2 upregulates HLA-DP, leading to CD8+ T cell exhaustion, and combined anti-LAG-3 and anti-PD-1 therapy improves anti-cancer efficacy.