{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:06:38Z","timestamp":1790820398554,"version":"4.1.0"},"reference-count":189,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2212Ottawa tools, with detailed risk\u2212of\u2212bias summaries provided in the Supplementary Materials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>EBV establishes hierarchical immunosuppression in NPC. Latent proteins LMP1, LMP2A, and EBNA1, together with non\u2212coding RNAs (BART miRNAs, EBERs), constitutively activate NF\u2212\u03baB, PI3K\/AKT\/mTOR, and JAK\/STAT pathways; LMP1 further promotes exosomal secretion and metabolic reprogramming that expands myeloid\u2212derived suppressor cells. Lytic\u2212phase 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\u2014immune\u2212excluded fibrotic stroma, immunosuppressive interface, tertiary lymphoid structures, vascular niches, and hypoxic tumor cores. Anti\u2212PD\u22121\u2212based chemo\u2212immunotherapy achieves 20\u201391% objective response rates and is now the first\u2212line standard for recurrent\/metastatic disease, as established by the JUPITER\u221202 and RATIONALE\u2212309 trials. EBV\u2212directed adoptive cell therapies, therapeutic vaccines, lytic induction, and stromal modulators have shown early promise, although definitive efficacy data are still lacking. Biomarker integration\u2014including plasma EBV DNA, viral genetic variants, spatial omics, and liquid biopsy\u2014offers potential for patient stratification, yet most emerging markers remain investigational.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This comprehensive review provides an evidence\u2212based framework linking EBV latent and lytic mechanisms to TME remodeling and precision therapeutics. Key limitations include over\u2212reliance on descriptive studies and insufficient functional validation of viral polymorphisms. Future research should prioritize spatial multi\u2212omics, isogenic viral systems, humanized models, and adaptive trial designs to advance mechanism\u2212driven therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/<\/jats:ext-link>\n                      , identifier CRD420261421334.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1875687","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T11:49:10Z","timestamp":1781869750000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Epstein\u2013Barr virus-driven immunosuppression in nasopharyngeal carcinoma: a comprehensive review of viral mechanisms, spatial tumor ecosystems, and precision therapeutics"],"prefix":"10.3389","volume":"17","author":[{"given":"Huiwen","family":"Qu","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Suzhou Ninth People\u2019s Hospital","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panpan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Suzhou Ninth People\u2019s Hospital","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yemei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Suzhou Ninth People\u2019s Hospital","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Suzhou Ninth People\u2019s Hospital","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.4193\/Rhin25.274","article-title":"EBV genome-guided transcriptomic re-annotation reveals molecular subtypes of nasopharyngeal carcinoma informing prognosis and treatment","volume":"64","author":"Ding","year":"2025","journal-title":"Rhinology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1455613241282410","DOI":"10.1177\/01455613241282410","article-title":"Racial disparities in nasopharyngeal carcinoma characteristics and survival","author":"Yu","year":"2024","journal-title":"Ear Nose Throat J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics15182292","article-title":"Evaluation of CK8\/18 and CK19 expression as adjunct immunohistochemical markers in non-keratinizing nasopharyngeal carcinoma","volume":"15","author":"Omar","year":"2025","journal-title":"Diagn 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