Nasopharyngeal carcinoma (NPC) is a distinct malignancy of the nasopharynx and is consistently associated with the Epstein-Barr virus (EBV) infection. Its unique anatomical location and complex aetiology often result in advanced-stage disease at first diagnosis. While radiotherapy (RT) and chemotherapy have been the mainstays of treatment, they often fail to prevent tumour recurrence and metastasis, leading to high rates of treatment failure and mortality. Recent advancement in cell-based therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown great promise in hematological malignancies and are now being investigated for NPC. However, challenges such as targeting specific tumour antigens, limited T cell persistence and proliferation, and managing treatment-related toxicities must be addressed. Extensive research is needed to enhance the effectiveness and safety of these therapies, paving the way for their integration into standard clinical practice for better management of NPC and a better quality of life for human health.
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.