Nasopharyngeal carcinoma (NPC) is a strikingly endemic malignancy in southern China: although the region represents only ~2% of the global population, it accounts for nearly 40% of all NPC cases worldwide. Often referred to as the "Cantonese cancer," NPC has long posed a fundamental question in cancer epidemiology—what underlies its extraordinary geographic concentration? Previous studies have identified human variation and Epstein–Barr virus (EBV) infection as risk factors associated with NPC incidence.

On April 16, a collaborative team led by Miao XU from Sun Yat-sen University Cancer Center, Jianjun LIU from the Genome Institute of Singapore, Weiwei ZHAI from the Institute of Zoology of the Chinese Academy of Sciences, and Zhonghua LIU from Columbia University reported a major advance in Nature, providing new insight into this long-standing puzzle.

Using a generalized linear mixed model, the researchers developed a stepwise analytical framework to dissect genome-to-genome interactions between the human host and Epstein–Barr virus, while rigorously controlling for confounding factors arising from complex host and viral population structure. Their analyses reveal that NPC risk is not driven by host genetics or viral variation alone, but by their interaction. Specifically, risk is jointly determined by host HLA-A alleles and an EBV variant (85841 A>G) in the high-risk EBV strain.

Functional investigation further showed that this viral mutation alters the antigenic epitope of EBNA3B gene, modulating its presentation by HLA-A11:01. This, in turn, directly affects the ability of CD8⁺ T cells to recognize and eliminate EBV-infected cells. As a consequence, individuals infected with the high-risk EBV variant who lack HLA-A11:01 exhibit an approximately 17-fold increase in NPC risk—an effect far exceeding the contribution of either host or viral factors considered independently.

The study also traces the evolutionary origin of this high-risk EBV lineage. The authors provide evidence that, around 4,000 years ago, recombination between northern and southern EBV lineages occurred in southern China, giving rise to the present-day high-risk strain. This lineage appears to have gained a selective advantage and subsequently expanded clonally, and is now estimated to infect approximately 35% of individuals in the region, making it the dominant subtype.

Together, these findings identify a high-risk EBV subtype that contributes substantially to the elevated burden of NPC in southern China, and provide a conceptual framework for understanding host–virus co-evolution in cancer risk. The work also lays a foundation for future vaccine development. Importantly, the identification of host genetic features that modulate susceptibility to oncogenic EBV effects opens the door to integrated risk stratification strategies combining viral and host information. Looking ahead, targeted surveillance of high-risk populations may enable earlier detection and intervention, and these groups may represent key candidates for future vaccination and precision prevention efforts.

https://doi.org/10.1038/s41586-026-10416-8

Contact:

ZHAI Weiwei

Institute of Zoology, Chinese Academy of Sciences

Tel: 86-10-64807533

Email: weiweizhai@ioz.ac.cn

Web: http://english.ioz.cas.cn/