{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:54:09Z","timestamp":1792760049255,"version":"4.5.0"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004480","name":"Natural Science Foundation of Shanxi Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004480","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Smoking, alcohol consumption, and high-risk human papillomavirus (HPV) infection are recognized risk factors for laryngeal squamous cell carcinoma (LSCC); however, approximately 20%\u201330% of patients lack typical exposure histories. Furthermore, HPV-positive patients exhibit significant prognostic heterogeneity, suggesting the complexity of multifactorial synergistic carcinogenesis. Recent studies have indicated that the unique anatomy and microenvironment of the larynx may mediate synergistic interactions between pathogens such as Epstein\u2013Barr virus (EBV) and HPV. This functional \u201ctwo-hit\u201d model drives metabolic reprogramming, disrupts immune responses, and promotes immune evasion, thereby potentially fueling the malignant progression of LSCC. However, coexistence patterns and dynamic interaction mechanisms remain unclear. This systematic review of field advances aims to elucidate potential synergistic mechanisms between HPV and EBV, providing theoretical foundations for pathogen-based multitarget diagnostics and clinical treatment strategies to advance the precision prevention and treatment of LSCC.<\/jats:p>","DOI":"10.3389\/fcimb.2026.1768893","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:40:42Z","timestamp":1771569642000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Laryngeal squamous cell carcinoma: a functional \u201ctwo-hit\u201d model of papillomavirus\u2013Epstein\u2013Barr virus synergistic carcinogenesis"],"prefix":"10.3389","volume":"16","author":[{"given":"Fang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]},{"name":"The First Clinical Medical School of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Huangfu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1111\/febs.14577","article-title":"Glucose transporters in cancer \u2013 from tumor cells to the tumor microenvironment","volume":"285","author":"Ancey","year":"2018","journal-title":"FEBS J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.radonc.2019.05.013","article-title":"Locally advanced hypopharyngeal and laryngeal cancer: Influence of HPV status","volume":"140","author":"Bates","year":"2019","journal-title":"Radiother. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.virol.2010.03.014","article-title":"Epstein-barr virus BRLF1 inhibits transcription of IRF3 and IRF7 and suppresses induction of interferon-\u03b2","volume":"402","author":"Bentz","year":"2010","journal-title":"Virology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cytogfr.2017.03.002","article-title":"The role of interleukin 10 in human papilloma virus infection and progression to cervical carcinoma","volume":"34","author":"Berti","year":"2017","journal-title":"Cytokine Growth Factor Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA. Cancer J. Clin."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3985","DOI":"10.3892\/ol.2018.7772","article-title":"IL-10 in the microenvironment of HNSCC inhibits the CpG ODN induced IFN-\u03b1 secretion of pDCs","volume":"15","author":"Bruchhage","year":"2018","journal-title":"Oncol. Lett."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/v14112372","article-title":"How EBV infects: the tropism and underlying molecular mechanism for viral infection","volume":"14","author":"Bu","year":"2022","journal-title":"Viruses"},{"key":"B8","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s10552-020-01287-z","article-title":"Risk of abnormal cervical cytology in HIV-infected women testing positive for both human papillomavirus and epstein-barr virus in genital tract specimens","volume":"31","author":"Cameron","year":"2020","journal-title":"Cancer Causes Control CCC"},{"key":"B9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41392-020-00376-4","article-title":"Targeting the signaling in Epstein\u2013Barr virus-associated diseases: mechanism, regulation, and clinical study","volume":"6","author":"Cao","year":"2021","journal-title":"Signal Transduction Targeting Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e33585","DOI":"10.1371\/journal.pone.0033585","article-title":"HPV16 oncoproteins induce MMPs\/RECK-TIMP-2 imbalance in primary keratinocytes: possible implications in cervical carcinogenesis","volume":"7","author":"Cardeal","year":"2012","journal-title":"PloS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1056\/NEJMoa1701717","article-title":"Analysis of plasma epstein\u2013barr virus DNA to screen for nasopharyngeal cancer","volume":"377","author":"Chan","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25073834","article-title":"The clinical relevance of the EPH\/ephrin signaling pathway in pediatric solid and hematologic Malignancies","volume":"25","author":"Chatzikalil","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"141600","DOI":"10.1016\/j.ijbiomac.2025.141600","article-title":"BSRF1 modulates IFN-\u03b2-mediated antiviral responses by inhibiting NF-\u03baB activity via an IKK-dependent mechanism in Epstein-Barr virus infection","volume":"306","author":"Chen","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231911943","article-title":"Lactate-lactylation hands between metabolic reprogramming and immunosuppression","volume":"23","author":"Chen","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e008375","DOI":"10.1136\/jitc-2023-008375","article-title":"EBV promotes TCR-T-cell therapy resistance by inducing CD163+M2 macrophage polarization and MMP9 secretion","volume":"12","author":"Chen","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"B16","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s12929-019-0568-z","article-title":"Tumor-associated macrophages: an accomplice in solid tumor progression","volume":"26","author":"Chen","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12943-024-01956-6","article-title":"Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison","volume":"23","author":"Cheng","year":"2024","journal-title":"Mol. Cancer"},{"key":"B17","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1186\/s12935-021-02024-5","article-title":"A review on the advances and challenges of immunotherapy for head and neck cancer","volume":"21","author":"Cheng","year":"2021","journal-title":"Cancer Cell Int."},{"key":"B19","doi-asserted-by":"publisher","first-page":"4682","DOI":"10.1158\/1078-0432.CCR-19-0211","article-title":"Rapid clearance profile of plasma circulating tumor HPV type 16 DNA during chemoradiotherapy correlates with disease control in HPV-associated oropharyngeal cancer","volume":"25","author":"Chera","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvoice.2025.03.006","article-title":"Accuracy of ChatGPT-4o in text and video analysis of laryngeal Malignant and premalignant diseases","author":"Chiesa-Estomba","year":"2025","journal-title":"J. Voice Off. J. Voice Found"},{"key":"B21","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1056\/NEJMra1715715","article-title":"Head and neck cancer","volume":"382","author":"Chow","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9040292","article-title":"Subversion of host innate immunity by human papillomavirus oncoproteins","volume":"9","author":"Cigno","year":"2020","journal-title":"Pathogens"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e42072","DOI":"10.1371\/journal.pone.0042072","article-title":"Epstein-barr virus immortalization of human B-cells leads to stabilization of hypoxia-induced factor 1 alpha, congruent with the warburg effect","volume":"7","author":"Darekar","year":"2012","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3654","DOI":"10.1128\/JVI.01888-07","article-title":"Epstein-barr virus-encoded LMP1 regulates epithelial cell motility and invasion via the ERK-MAPK pathway","volume":"82","author":"Dawson","year":"2008","journal-title":"J. Virol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s13046-017-0541-1","article-title":"hrHPV E5 oncoprotein: immune evasion and related immunotherapies","volume":"36","author":"de Freitas","year":"2017","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10111429","article-title":"Epstein-barr virus-associated carcinoma of the larynx: a systematic review with meta-analysis","volume":"10","author":"de Lima","year":"2021","journal-title":"Pathog. Basel Switz."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122752","article-title":"Coinfection with epstein\u2013barr virus (EBV), human papilloma virus (HPV) and polyoma BK virus (BKPyV) in laryngeal, oropharyngeal and oral cavity cancer","volume":"18","author":"Drop","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"10715","DOI":"10.1021\/acs.jmedchem.3c00907","article-title":"Discovery and optimization of a STING agonist platform for application in antibody drug conjugates","volume":"66","author":"Duvall","year":"2023","journal-title":"J. Med. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s40164-024-00570-y","article-title":"CRISPR\/Cas9 technology for advancements in cancer immunotherapy: from uncovering regulatory mechanisms to therapeutic applications","volume":"13","author":"Feng","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1182\/blood-2006-07-035972","article-title":"Inhibitory effect of tumor cell\u2013derived lactic acid on human T cells","volume":"109","author":"Fischer","year":"2007","journal-title":"Blood"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1126\/science.3103217","article-title":"Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes","volume":"235","author":"Flier","year":"1987","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-12-38","article-title":"Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway","volume":"12","author":"French","year":"2013","journal-title":"Mol. Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2130","DOI":"10.1016\/j.ejca.2015.07.043","article-title":"Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study","volume":"51","author":"Gatta","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"4930","DOI":"10.1038\/sj.onc.1203860","article-title":"Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins","volume":"19","author":"Georgopoulos","year":"2000","journal-title":"Oncogene"},{"key":"B35","first-page":"3188","article-title":"Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells","volume":"160","author":"Groux","year":"1998","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e01216","DOI":"10.1128\/JVI.01216-18","article-title":"Inhibition of epstein-barr virus replication in human papillomavirus-immortalized keratinocytes","volume":"93","author":"Guidry","year":"2019","journal-title":"J. Virol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1182\/bloodadvances.2018025536","article-title":"Plasmacytoid dendritic cells respond to Epstein-Barr virus infection with a distinct type I interferon subtype profile","volume":"3","author":"Gujer","year":"2019","journal-title":"Blood Adv."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e1005747","DOI":"10.1371\/journal.ppat.1005747","article-title":"Post-transcriptional regulation of KLF4 by high-risk human papillomaviruses is necessary for the differentiation-dependent viral life cycle","volume":"12","author":"Gunasekharan","year":"2016","journal-title":"PloS Pathog."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9060452","article-title":"High-risk human papillomaviruses and epstein\u2013barr virus in colorectal cancer and their association with clinicopathological status","volume":"9","author":"Gupta","year":"2020","journal-title":"Pathogens"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01016","article-title":"Co-incidence of human papillomaviruses and epstein\u2013barr virus is associated with high to intermediate tumor grade in human head and neck cancer in Syria","volume":"10","author":"Gupta","year":"2020","journal-title":"Front. Oncol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.currproblcancer.2018.03.003","article-title":"HPV: Molecular pathways and targets","volume":"42","author":"Gupta","year":"2018","journal-title":"Curr. Probl. Cancer"},{"key":"B42","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1084\/jem.20122394","article-title":"The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter","volume":"210","author":"Hasan","year":"2013","journal-title":"J. Exp. Med."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241814072","article-title":"Epstein-barr virus promotes oral squamous cell carcinoma stemness through the warburg effect","volume":"24","author":"Heawchaiyaphum","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"6921","DOI":"10.1158\/0008-5472.CAN-11-1457","article-title":"Lactate: a metabolic key player in cancer","volume":"71","author":"Hirschhaeuser","year":"2011","journal-title":"Cancer Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"4062","DOI":"10.4049\/jimmunol.1501605","article-title":"EBV MicroRNA BART16 suppresses type I IFN signaling","volume":"198","author":"Hooykaas","year":"2017","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.4049\/jimmunol.0803218","article-title":"Specific targeting of the EBV lytic phase protein BNLF2a to the transporter associated with antigen processing results in impairment of HLA class I-restricted antigen presentation","volume":"182","author":"Horst","year":"2009","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"B49","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1097\/JS9.0000000000000902","article-title":"Updated disease distributions, risk factors, and trends of laryngeal cancer: a global analysis of cancer registries","volume":"110","author":"Huang","year":"2023","journal-title":"Int. J. Surg. Lond. Engl."},{"key":"B48","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.ijrobp.2019.01.007","article-title":"Plasma epstein-barr virus DNA load after induction chemotherapy predicts outcome in locoregionally advanced nasopharyngeal carcinoma","volume":"104","author":"Huang","year":"2019","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"B50","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1186\/s12967-025-06843-2","article-title":"The cGAS-STING pathway: a dual regulator of immune response in cancer and therapeutic implications","volume":"23","author":"Huang","year":"2025","journal-title":"J. Transl. Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.semcancer.2017.06.001","article-title":"The JAK\/STAT3 axis: a comprehensive drug target for solid Malignancies","volume":"45","author":"Huynh","year":"2017","journal-title":"Semin. Cancer Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"7836","DOI":"10.1128\/JVI.01197-10","article-title":"Transforming growth factor \u03b2-induced reactivation of epstein-barr virus involves multiple smad-binding elements cooperatively activating expression of the latent-lytic switch BZLF1 gene","volume":"85","author":"Iempridee","year":"2011","journal-title":"J. Virol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"13154","DOI":"10.1038\/s41598-020-70129-4","article-title":"TLR4 896A\/G and TLR9 1174G\/a polymorphisms are associated with the risk of infectious mononucleosis","volume":"10","author":"Jab\u0142o\u0144ska","year":"2020","journal-title":"Sci. Rep."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e2045","DOI":"10.1002\/cnr2.2045","article-title":"Developments and future prospects of personalized medicine in head and neck squamous cell carcinoma diagnoses and treatments","volume":"7","author":"Jayawickrama","year":"2024","journal-title":"Cancer Rep."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/srep34789","article-title":"Suppression of the CD8 T cell response by human papillomavirus type 16 E7 occurs in langerhans cell-depleted mice","volume":"6","author":"Jemon","year":"2016","journal-title":"Sci. Rep."},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.120711","article-title":"Enhanced response to PD-L1 silencing by modulation of TME via balancing glucose metabolism and robust co-delivery of siRNA\/resveratrol with dual-responsive polyplexes","volume":"271","author":"Jia","year":"2021","journal-title":"Biomaterials"},{"key":"B57","doi-asserted-by":"publisher","first-page":"e1002704","DOI":"10.1371\/journal.ppat.1002704","article-title":"The EBV immunoevasins vIL-10 and BNLF2a protect newly infected B cells from immune recognition and elimination","volume":"8","author":"Jochum","year":"2012","journal-title":"PloS Pathog."},{"key":"B58","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1590\/S1517-83822012000200039","article-title":"Correlation between ebv co-infection and HPV16 genome integrity in Tunisian cervical cancer patients","volume":"43","author":"Kahla","year":"2012","journal-title":"Braz. J. Microbiol."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11071712","article-title":"Suppression of nasopharyngeal and gastric tumor growth in a mouse model by antibodies to epstein\u2013barr virus LMP1 protein","volume":"11","author":"Khenchouche","year":"2023","journal-title":"Microorganisms"},{"key":"B60","doi-asserted-by":"publisher","first-page":"89681","DOI":"10.18632\/oncotarget.20813","article-title":"Hypoxia-inducible factor-1\u03b1 activation in HPV-positive head and neck squamous cell carcinoma cell lines","volume":"8","author":"Knuth","year":"2017","journal-title":"Oncotarget"},{"key":"B61","doi-asserted-by":"publisher","first-page":"2341","DOI":"10.1007\/s00432-017-2481-8","article-title":"Prognostic implications of human papillomavirus status for patients with non-oropharyngeal head and neck squamous cell carcinomas","volume":"143","author":"Ko","year":"2017","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"9870","DOI":"10.1158\/0008-5472.CAN-06-1679","article-title":"EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1\u03b1 through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells","volume":"66","author":"Kondo","year":"2006","journal-title":"Cancer Res."},{"key":"B63","doi-asserted-by":"publisher","first-page":"eaan5488","DOI":"10.1126\/scitranslmed.aan5488","article-title":"Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-\u03b2","volume":"10","author":"Lan","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"B65","doi-asserted-by":"publisher","first-page":"497","DOI":"10.4049\/jimmunol.167.1.497","article-title":"Both E6 and E7 oncoproteins of human papillomavirus 16 inhibit IL-18-induced IFN-gamma production in human peripheral blood mononuclear and NK cells","volume":"167","author":"Lee","year":"2001","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"B64","doi-asserted-by":"publisher","first-page":"e29386","DOI":"10.1002\/jmv.29386","article-title":"Deciphering head and neck cancer microenvironment: single-cell and spatial transcriptomics reveals human papillomavirus-associated differences","volume":"96","author":"Lee","year":"2024","journal-title":"J. Med. Virol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/375685a0","article-title":"Inhibition of antigen processing by the internal repeat region of the epstein-barr virus nuclear antigen-1","volume":"375","author":"Levitskaya","year":"1995","journal-title":"Nature"},{"key":"B67","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s12943-020-01234-1","article-title":"Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects","volume":"19","author":"Li","year":"2020","journal-title":"Mol. Cancer"},{"key":"B69","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/s12964-024-01562-5","article-title":"The enhanced antitumor activity of bispecific antibody targeting PD-1\/PD-L1 signaling","volume":"22","author":"Li","year":"2024","journal-title":"Cell Commun. Signal. CCS"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1549766","article-title":"Human papillomavirus E1 proteins inhibit RIG-I\/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity","volume":"16","author":"Li","year":"2025","journal-title":"Front. Immunol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"23345","DOI":"10.1074\/jbc.M107420200","article-title":"Epstein-barr virus BZLF1 gene is activated by transforming growth factor-beta through cooperativity of smads and c-jun\/c-fos proteins","volume":"277","author":"Liang","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1186\/2042-4280-5-1","article-title":"Epstein-barr virus IL-10 gene expression by a recombinant murine gammaherpesvirus in vivo enhances acute pathogenicity but does not affect latency or reactivation","volume":"5","author":"Lindquester","year":"2014","journal-title":"Herpesviridae"},{"key":"B73","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1186\/s12935-021-01862-7","article-title":"The diagnostic value of EBV-DNA and EBV-related antibodies detection for nasopharyngeal carcinoma: a meta-analysis","volume":"21","author":"Liu","year":"2021","journal-title":"Cancer Cell Int."},{"key":"B72","doi-asserted-by":"publisher","first-page":"e1002690","DOI":"10.1371\/journal.ppat.1002690","article-title":"Epstein-barr virus-encoded LMP1 interacts with FGD4 to activate Cdc42 and thereby promote migration of nasopharyngeal carcinoma cells","volume":"8","author":"Liu","year":"2012","journal-title":"PloS Pathog."},{"key":"B74","doi-asserted-by":"publisher","first-page":"ra15","DOI":"10.1126\/scisignal.aac5820","article-title":"Phosphoproteomic analysis of tumor-endothelial signaling identifies EPHA2 as a negative regulator of transendothelial migration","volume":"9","author":"Locard-Paulet","year":"2016","journal-title":"Sci. Signal."},{"key":"B75","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1159\/000479749","article-title":"Epstein-barr virus miR-BART6-3p inhibits the RIG-I pathway","volume":"9","author":"Lu","year":"2017","journal-title":"J. Innate Immun."},{"key":"B76","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1158\/1078-0432.CCR-23-0118","article-title":"Phase I study of SYNB1891, an engineered E. coli nissle strain expressing STING agonist, with and without atezolizumab in advanced Malignancies","volume":"29","author":"Luke","year":"2023","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"B77","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1172\/JCI129497","article-title":"HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING","volume":"130","author":"Luo","year":"2020","journal-title":"J. Clin. Invest."},{"key":"B78","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.virol.2016.05.005","article-title":"Human papillomavirus promotes epstein-barr virus maintenance and lytic reactivation in immortalized oral keratinocytes","volume":"495","author":"Makielski","year":"2016","journal-title":"Virology"},{"key":"B79","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1158\/1078-0432.CCR-22-2235","article-title":"Combination of the STING agonist MIW815 (ADU-S100) and PD-1 inhibitor spartalizumab in advanced\/metastatic solid tumors or lymphomas: an open-label, multicenter, phase ib study","volume":"29","author":"Meric-Bernstam","year":"2023","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"B80","doi-asserted-by":"publisher","first-page":"e0120426","DOI":"10.1371\/journal.pone.0120426","article-title":"Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells","volume":"10","author":"Mi","year":"2015","journal-title":"PloS One"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/20503121211069012","article-title":"Tumor promoting roles of IL-10, TGF-\u03b2, IL-4, and IL-35: its implications in cancer immunotherapy","volume":"10","author":"Mirlekar","year":"2022","journal-title":"SAGE Open Med."},{"key":"B82","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1186\/s12885-021-08658-y","article-title":"Possible role of HPV\/EBV coinfection in anoikis resistance and development in prostate cancer","volume":"21","author":"Nahand","year":"2021","journal-title":"BMC Cancer"},{"key":"B83","doi-asserted-by":"publisher","first-page":"e1005195","DOI":"10.1371\/journal.ppat.1005195","article-title":"Differentiation-dependent KLF4 expression promotes lytic epstein-barr virus infection in epithelial cells","volume":"11","author":"Nawandar","year":"2015","journal-title":"PloS Pathog."},{"key":"B84","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1177\/0194599820976178","article-title":"Prognostic significance of HPV status in laryngeal squamous cell carcinoma: a large-population database study","volume":"165","author":"Panuganti","year":"2021","journal-title":"Otolaryngol.--Head Neck Surg. Off. J. Am. Acad. Otolaryngol.-Head Neck Surg."},{"key":"B85","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1016\/j.semcancer.2022.09.007","article-title":"Tumor glycolysis, an essential sweet tooth of tumor cells","volume":"86","author":"Paul","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"5255","DOI":"10.3390\/curroncol31090389","article-title":"Artificial intelligence in head and neck cancer: innovations, applications, and future directions","volume":"31","author":"Pham","year":"2024","journal-title":"Curr. Oncol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1111\/joim.12016","article-title":"Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force","volume":"273","author":"Polet","year":"2013","journal-title":"J. Intern. Med."},{"key":"B88","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrc2541","article-title":"Toll-like receptors and cancer","volume":"9","author":"Rakoff-Nahoum","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"B89","doi-asserted-by":"publisher","first-page":"3247","DOI":"10.21873\/anticanres.15110","article-title":"Cytokine-based cancer immunotherapy: challenges and opportunities for IL-10","volume":"41","author":"Rallis","year":"2021","journal-title":"Anticancer Res."},{"key":"B90","doi-asserted-by":"publisher","first-page":"11372","DOI":"10.1128\/JVI.05279-11","article-title":"High-risk human papillomaviruses repress constitutive kappa interferon transcription via E6 to prevent pathogen recognition receptor and antiviral-gene expression","volume":"85","author":"Reiser","year":"2011","journal-title":"J. Virol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"11583","DOI":"10.1073\/pnas.2034960100","article-title":"Interference with T cell receptor-HLA-DR interactions by epstein-barr virus gp42 results in reduced T helper cell recognition","volume":"100","author":"Ressing","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B92","doi-asserted-by":"publisher","first-page":"3366","DOI":"10.1073\/pnas.0611128104","article-title":"Host shutoff during productive epstein\u2013barr virus infection is mediated by BGLF5 and May contribute to immune evasion","volume":"104","author":"Rowe","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B93","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1006\/viro.2002.1716","article-title":"Epstein\u2013barr virus encoded interleukin-10 inhibits HLA-class I, ICAM-1, and B7 expression on human monocytes: implications for immune evasion by EBV","volume":"304","author":"Salek-Ardakani","year":"2002","journal-title":"Virology"},{"key":"B94","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1007\/s12672-022-00475-4","article-title":"Mapping human papillomavirus, Epstein\u2013Barr virus, cytomegalovirus, adenovirus, and p16 in laryngeal cancer","volume":"13","author":"Schindele","year":"2022","journal-title":"Discov. Oncol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"e01582","DOI":"10.1128\/JVI.01582-19","article-title":"Human papillomavirus 16 E5 inhibits interferon signaling and supports episomal viral maintenance","volume":"94","author":"Scott","year":"2020","journal-title":"J. Virol."},{"key":"B96","first-page":"1920","article-title":"Dual expression of epstein-barr virus, latent membrane protein-1 and human papillomavirus-16 E6 transform primary mouse embryonic fibroblasts through NF-\u03baB signaling","volume":"7","author":"Shimabuku","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1405318","article-title":"Differential tumor immune microenvironment coupled with tumor progression or tumor eradication in HPV-antigen expressing squamous cell carcinoma (SCC) models","volume":"15","author":"Shivarudrappa","year":"2024","journal-title":"Front. Immunol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"e1012934","DOI":"10.1371\/journal.ppat.1012934","article-title":"Inhibition of the integrated stress response by epstein-barr virus oncoprotein LMP1 attenuates epithelial cell differentiation and lytic viral reactivation","volume":"21","author":"Singh","year":"2025","journal-title":"PloS Pathog."},{"key":"B100","doi-asserted-by":"publisher","first-page":"3074","DOI":"10.1016\/j.celrep.2018.11.047","article-title":"Magnitude of therapeutic STING activation determines CD8+ T cell-mediated anti-tumor immunity","volume":"25","author":"Sivick","year":"2018","journal-title":"Cell Rep."},{"key":"B101","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/0042-6822(92)90253-l","article-title":"The interleukin-10 homolog encoded by epstein-barr virus enhances the reactivation of virus-specific cytotoxic T cell and HLA-unrestricted killer cell responses","volume":"191","author":"Stewart","year":"1992","journal-title":"Virology"},{"key":"B102","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1158\/1078-0432.CCR-17-2653","article-title":"Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF\u03b2, in advanced solid tumors","volume":"24","author":"Strauss","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"B103","doi-asserted-by":"publisher","first-page":"3859","DOI":"10.3892\/mmr.2017.8307","article-title":"Competing endogenous RNA network analysis of CD274, IL\u221210 and FOXP3 co\u2212expression in laryngeal squamous cell carcinoma","volume":"17","author":"Sun","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"B104","doi-asserted-by":"crossref","first-page":"337","DOI":"10.18388\/abp.2009_2466","article-title":"Herpesviruses as possible cofactors in HPV-16-related oncogenesis","volume":"56","author":"Szostek","year":"2009","journal-title":"Acta Biochim. Pol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1002\/ohn.1056","article-title":"Methodology of cfHPV-DNA detection in head and neck cancer: a systematic review and meta-analysis","volume":"172","author":"Thomas","year":"2025","journal-title":"Otolaryngol. Neck Surg."},{"key":"B106","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/s41392-025-02280-1","article-title":"Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches","volume":"10","author":"Tufail","year":"2025","journal-title":"Signal Transduction Targeting Ther."},{"key":"B107","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1186\/s12885-021-08397-0","article-title":"Co-expression of low-risk HPV E6\/E7 and EBV LMP-1 leads to precancerous lesions by DNA damage","volume":"21","author":"Uehara","year":"2021","journal-title":"BMC Cancer"},{"key":"B108","doi-asserted-by":"publisher","first-page":"e5834","DOI":"10.7717\/peerj.5834","article-title":"Infection and coinfection by human papillomavirus, epstein\u2013barr virus and merkel cell polyomavirus in patients with squamous cell carcinoma of the larynx: a retrospective study","volume":"6","author":"Vazquez-Guillen","year":"2018","journal-title":"PeerJ"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10080247","article-title":"The dynamic roles of TGF-\u03b2 signalling in EBV-associated cancers","volume":"10","author":"Velapasamy","year":"2018","journal-title":"Cancers"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.513383","article-title":"Epstein-barr virus early protein BFRF1 suppresses IFN-\u03b2 Activity by inhibiting the activation of IRF3","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Immunol."},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00830","article-title":"Targeting head and neck cancer by vaccination","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Immunol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1128\/jvi.01099-08","article-title":"Epstein-barr virus BGLF4 kinase suppresses the interferon regulatory factor 3 signaling pathway","volume":"83","author":"Wang","year":"2009","journal-title":"J. Virol."},{"key":"B114","first-page":"33","article-title":"Papillomaviruses: HPV as the etiological factor of head and neck cancers","volume":"57","author":"Wicinski","year":"2018","journal-title":"Postepy Mikrobiol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1128\/jvi.00602-08","article-title":"Epstein-barr virus LF2: an antagonist to type I interferon","volume":"83","author":"Wu","year":"2009","journal-title":"J. Virol."},{"key":"B116","doi-asserted-by":"publisher","first-page":"5123","DOI":"10.7150\/thno.100171","article-title":"EBV-associated epithelial cancers cells promote vasculogenic mimicry formation via a secretory cross-talk with the immune microenvironment","volume":"14","author":"Xiang","year":"2024","journal-title":"Theranostics"},{"key":"B117","doi-asserted-by":"publisher","first-page":"4568","DOI":"10.1038\/onc.2014.32","article-title":"Targeting epstein\u2013barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy","volume":"33","author":"Xiao","year":"2014","journal-title":"Oncogene"},{"key":"B118","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.virs.2022.09.001","article-title":"Cyclophilin a binds to AKT1 and facilitates the tumorigenicity of epstein-barr virus by mediating the activation of AKT\/mTOR\/NF-\u03baB positive feedback loop","volume":"37","author":"Xin","year":"2022","journal-title":"Virol. Sin."},{"key":"B119","doi-asserted-by":"publisher","first-page":"4455","DOI":"10.7150\/jca.34016","article-title":"Effect of HPV infection on the occurrence and development of laryngeal cancer: a review","volume":"10","author":"Yang","year":"2019","journal-title":"J. Cancer"},{"key":"B121","doi-asserted-by":"publisher","first-page":"e02168","DOI":"10.1128\/JVI.02168-16","article-title":"Epstein-barr virus-encoded latent membrane protein 1 upregulates glucose transporter 1 transcription via the mTORC1\/NF-\u03baB signaling pathways","volume":"91","author":"Zhang","year":"2017","journal-title":"J. Virol."},{"key":"B120","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s41586-023-06256-5","article-title":"Reprogramming tumour-associated macrophages to outcompete cancer cells","volume":"619","author":"Zhang","year":"2023","journal-title":"Nature"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107226","article-title":"Epstein-barr virus suppresses N6-methyladenosine modification of TLR9 to promote immune evasion","volume":"300","author":"Zhang","year":"2024","journal-title":"J. Biol. Chem."},{"key":"B123","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41392-024-02083-w","article-title":"Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use","volume":"10","author":"Zhang","year":"2025","journal-title":"Signal Transduction Targeting Ther."},{"key":"B124","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/s41577-024-01112-7","article-title":"Regulation of cGAS\u2013STING signalling and its diversity of cellular outcomes","volume":"25","author":"Zhang","year":"2025","journal-title":"Nat. Rev. Immunol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1768893\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:40:44Z","timestamp":1771569644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1768893\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,20]]},"references-count":122,"alternative-id":["10.3389\/fcimb.2026.1768893"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1768893","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,20]]},"article-number":"1768893"}}