Epstein-Barr virus-driven immunosuppression in nasopharyngeal carcinoma: a comprehensive review of viral mechanisms, spatial tumor ecosystems, and precision therapeutics.

Background: EBV infection is the defining etiological factor in nasopharyngeal carcinoma (NPC), yet how viral factors systematically remodel the tumor immune microenvironment (TME) to sustain immunosuppression remains incompletely characterized. Existing reviews lack an integrated synthesis of viral mechanisms, TME spatial architecture, and therapeutic translation. Methods: We conducted a comprehensive literature search across PubMed, Embase, and Web of Science from inception to December 2025, with an update check to May 2026, following PRISMA guidelines. Given the broad scope, a narrative synthesis was adopted rather than a formal systematic review. Two reviewers independently screened 4,235 records, and 182 studies were included. Methodological quality was assessed using Cochrane RoB 2 and Newcastle-Ottawa tools, with detailed risk-of-bias summaries provided in the Supplementary Materials. Results: EBV establishes hierarchical immunosuppression in NPC. Latent proteins LMP1, LMP2A, and EBNA1, together with non-coding RNAs (BART miRNAs, EBERs), constitutively activate NF-κB, PI3K/AKT/mTOR, and JAK/STAT pathways; LMP1 further promotes exosomal secretion and metabolic reprogramming that expands myeloid-derived suppressor cells. Lytic-phase genetic polymorphisms in BALF2, BZLF1, and BRLF1 are associated with differential immune signatures, though these associations remain correlative and lack functional validation. Based on limited spatial profiling studies, the TME can be provisionally conceptualized as five distinct immunosuppressive niches-immune-excluded fibrotic stroma, immunosuppressive interface, tertiary lymphoid structures, vascular niches, and hypoxic tumor cores. Anti-PD-1-based chemo-immunotherapy achieves 20-91% objective response rates and is now the first-line standard for recurrent/metastatic disease, as established by the JUPITER-02 and RATIONALE-309 trials. EBV-directed adoptive cell therapies, therapeutic vaccines, lytic induction, and stromal modulators have shown early promise, although definitive efficacy data are still lacking. Biomarker integration-including plasma EBV DNA, viral genetic variants, spatial omics, and liquid biopsy-offers potential for patient stratification, yet most emerging markers remain investigational. Conclusions: This comprehensive review provides an evidence-based framework linking EBV latent and lytic mechanisms to TME remodeling and precision therapeutics. Key limitations include over-reliance on descriptive studies and insufficient functional validation of viral polymorphisms. Future research should prioritize spatial multi-omics, isogenic viral systems, humanized models, and adaptive trial designs to advance mechanism-driven therapy. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261421334.