Yang, J. D. et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol. 16, 589–604 (2019).
Google Scholar
Malagon, T., Franco, E. L., Tejada, R. & Vaccarella, S. Epidemiology of HPV-associated cancers past, present and future: towards prevention and elimination. Nat. Rev. Clin. Oncol. 21, 522–538 (2024).
Google Scholar
Young, L. S., Yap, L. F. & Murray, P. G. Epstein–Barr virus: more than 50 years old and still providing surprises. Nat. Rev. Cancer 16, 789–802 (2016).
Google Scholar
Becker, J. C. et al. Merkel cell carcinoma. Nat. Rev. Dis. Primers 3, 17077 (2017).
Google Scholar
Matsuoka, M. & Jeang, K. T. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat. Rev. Cancer 7, 270–280 (2007).
Google Scholar
Mesri, E. A., Cesarman, E. & Boshoff, C. Kaposi’s sarcoma and its associated herpesvirus. Nat. Rev. Cancer 10, 707–719 (2010).
Google Scholar
Moore, P. S. & Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer 10, 878–889 (2010). A landmark synthesis tracing the history of tumour virology research from early animal models to validated human oncogenic viruses, essential for understanding how the concept developed historically.
Google Scholar
Bravo, I. G. & Felez-Sanchez, M. Papillomaviruses: viral evolution, cancer and evolutionary medicine. Evol. Med. Public Health 2015, 32–51 (2015). This study provides a framework to understand viral evolution using HPVs as examples.
Google Scholar
Ashrafi, G. H., Haghshenas, M., Marchetti, B. & Campo, M. S. E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain. Int. J. Cancer 119, 2105–2112 (2006).
Google Scholar
Yi, J. S., Cox, M. A. & Zajac, A. J. T-cell exhaustion: characteristics, causes and conversion. Immunology 129, 474–481 (2010).
Google Scholar
Gregory, C. D. et al. Activation of Epstein–Barr virus latent genes protects human B cells from death by apoptosis. Nature 349, 612–614 (1991).
Google Scholar
Parkin, D. M. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030–3044 (2006).
Google Scholar
Plummer, M. et al. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob. Health 4, e609–e616 (2016).
Google Scholar
de Martel, C., Georges, D., Bray, F., Ferlay, J. & Clifford, G. M. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob. Health 8, e180–e190 (2020). Along with Parkin et al. (2006) and Plummer et al. (2016), this study is a foundational longitudinal epidemiological analysis of infection-associated cancer globally, providing a quantitative assessment of the magnitude of the problem and motivating the further study of oncogenic viruses.
Google Scholar
Chang, M. H. et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan childhood hepatoma study group. N. Engl. J. Med. 336, 1855–1859 (1997). This study demonstrated that universal hepatitis B vaccination in Taiwan notably reduced childhood HCC incidence, providing the first proof that a viral vaccine could prevent a human cancer.
Google Scholar
Finn, O. J. The dawn of vaccines for cancer prevention. Nat. Rev. Immunol. 18, 183–194 (2018).
Google Scholar
Koonin, E. V., Dolja, V. V. & Krupovic, M. The healthy human virome: from virus-host symbiosis to disease. Curr. Opin. Virol. 47, 86–94 (2021). This study provides a conceptual framework for understanding the healthy human virome as a dynamic ecosystem shaped by virus–host symbiosis.
Google Scholar
Roossinck, M. J. & Bazan, E. R. Symbiosis: viruses as intimate partners. Annu. Rev. Virol. 4, 123–139 (2017).
Google Scholar
Jacqueline, C. et al. Infections and cancer: the “fifty shades of immunity” hypothesis. BMC Cancer 17, 257 (2017).
Google Scholar
Perry, S. et al. Infection with Helicobacter pylori is associated with protection against tuberculosis. PLoS ONE 5, e8804 (2010).
Google Scholar
Cobey, S. & Pascual, M. Consequences of host heterogeneity, epitope immunodominance, and immune breadth for strain competition. J. Theor. Biol. 270, 80–87 (2011).
Google Scholar
Finlay, B. B. & McFadden, G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124, 767–782 (2006).
Google Scholar
Fujinami, R. S., von Herrath, M. G., Christen, U. & Whitton, J. L. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin. Microbiol. Rev. 19, 80–94 (2006).
Google Scholar
Jankovic, M. et al. A potential oncoprotective role of cytomegalovirus against breast cancer: worldwide correlation and survey of evidence. Diseases 13, 181 (2025).
Google Scholar
Leng, Q., Tarbe, M., Long, Q. & Wang, F. Pre-existing heterologous T-cell immunity and neoantigen immunogenicity. Clin. Transl. Immunol. 9, e01111 (2020).
Google Scholar
Zitvogel, L. & Kroemer, G. Cross-reactivity between microbial and tumor antigens. Curr. Opin. Immunol. 75, 102171 (2022).
Google Scholar
Amirian, E. S. et al. History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC). Cancer Med. 5, 1352–1358 (2016).
Google Scholar
Wrensch, M. et al. History of chickenpox and shingles and prevalence of antibodies to varicella-zoster virus and three other herpesviruses among adults with glioma and controls. Am. J. Epidemiol. 161, 929–938 (2005).
Google Scholar
Cramer, D. W. et al. Mumps and ovarian cancer: modern interpretation of an historic association. Cancer Causes Control. 21, 1193–1201 (2010).
Google Scholar
Cramer, D. W. The epidemiology of endometrial and ovarian cancer. Hematol. Oncol. Clin. North Am. 26, 1–12 (2012).
Google Scholar
O’Malley, P. W., Mulla, Z. D. & Nesic, O. Multiple sclerosis and breast cancer. J. Neurol. Sci. 356, 137–141 (2015).
Google Scholar
Tengvall, K. et al. Molecular mimicry between anoctamin 2 and Epstein–Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proc. Natl Acad. Sci. USA 116, 16955–16960 (2019).
Google Scholar
Griffiths, D. J. Endogenous retroviruses in the human genome sequence. Genome Biol. 2, reviews1017.1–reviews1017.5 (2001).
Google Scholar
Wang, J., Lu, X., Zhang, W. & Liu, G. H. Endogenous retroviruses in development and health. Trends Microbiol. 32, 342–354 (2024).
Google Scholar
Suntsova, M. et al. Molecular functions of human endogenous retroviruses in health and disease. Cell Mol. Life Sci. 72, 3653–3675 (2015).
Google Scholar
Edwards, R. A. & Rohwer, F. Viral metagenomics. Nat. Rev. Microbiol. 3, 504–510 (2005).
Google Scholar
Virgin, H. W. The virome in mammalian physiology and disease. Cell 157, 142–150 (2014).
Google Scholar
Gregory, A. C. et al. The gut virome database reveals age-dependent patterns of virome diversity in the human gut. Cell Host Microbe 28, 724–740 e728 (2020).
Google Scholar
Li, S. et al. A catalog of 48,425 nonredundant viruses from oral metagenomes expands the horizon of the human oral virome. iScience 25, 104418 (2022).
Google Scholar
Li, Y. et al. Altered respiratory virome and serum cytokine profile associated with recurrent respiratory tract infections in children. Nat. Commun. 10, 2288 (2019).
Google Scholar
Feng, B. et al. An atlas of the blood virome in healthy individuals. Virus Res. 323, 199004 (2023).
Google Scholar
Li, Z. et al. A comprehensive reference catalog of human skin DNA virome reveals novel viral diversity and microenvironmental influences. Microbiol. Spectr. 13, e0117825 (2025).
Google Scholar
Garretto, A., Thomas-White, K., Wolfe, A. J. & Putonti, C. Detecting viral genomes in the female urinary microbiome. J. Gen. Virol. 99, 1141–1146 (2018).
Google Scholar
Dang, X. et al. Characterization of the brain virome in human immunodeficiency virus infection and substance use disorder. PLoS ONE 19, e0299891 (2024).
Google Scholar
Bhagchandani, T., Nikita, Verma, A. & Tandon, R. Exploring the human virome: composition, dynamics, and implications for health and disease. Curr. Microbiol. 81, 16 (2023).
Google Scholar
Wirbel, J. et al. Long-read metagenomics reveals phage dynamics in the human gut microbiome. Nature 649, 982–990 (2026).
Google Scholar
Borodovich, T., Shkoporov, A. N., Ross, R. P. & Hill, C. Phage-mediated horizontal gene transfer and its implications for the human gut microbiome. Gastroenterol. Rep. 10, goac012 (2022).
Google Scholar
Reyes, A., Wu, M., McNulty, N. P., Rohwer, F. L. & Gordon, J. I. Gnotobiotic mouse model of phage-bacterial host dynamics in the human gut. Proc. Natl Acad. Sci. USA 110, 20236–20241 (2013).
Google Scholar
Barr, J. J. A bacteriophages journey through the human body. Immunol. Rev. 279, 106–122 (2017).
Google Scholar
Kaczorowska, J. & van der Hoek, L. Human anelloviruses: diverse, omnipresent and commensal members of the virome. FEMS Microbiol. Rev. 44, 305–313 (2020).
Google Scholar
Cadwell, K. The virome in host health and disease. Immunity 42, 805–813 (2015).
Google Scholar
Reyes, A. et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466, 334–338 (2010).
Google Scholar
Hannigan, G. D. et al. The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. mBio 6, e01578–01515 (2015).
Google Scholar
Sedghi, L., DiMassa, V., Harrington, A., Lynch, S. V. & Kapila, Y. L. The oral microbiome: role of key organisms and complex networks in oral health and disease. Periodontol. 2000 87, 107–131 (2021).
Google Scholar
Doorbar, J. et al. The biology and life-cycle of human papillomaviruses. Vaccine 30, F55–F70 (2012).
Google Scholar
Shuda, M. et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc. Natl Acad. Sci. USA 105, 16272–16277 (2008).
Google Scholar
Chang, Y. & Moore, P. S. Merkel cell carcinoma: a virus-induced human cancer. Annu. Rev. Pathol. 7, 123–144 (2012).
Google Scholar
Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007). A landmark study demonstrating that latent herpesvirus infection confers broad protection against bacterial infection in mice, providing the first evidence of the beneficial effects of persistent viral infection on the host.
Google Scholar
Redpath, S., Angulo, A., Gascoigne, N. R. & Ghazal, P. Immune checkpoints in viral latency. Annu. Rev. Microbiol. 55, 531–560 (2001).
Google Scholar
Barr, J. N. & Fearns, R. How RNA viruses maintain their genome integrity. J. Gen. Virol. 91, 1373–1387 (2010).
Google Scholar
Hansen, T. H. & Bouvier, M. MHC class I antigen presentation: learning from viral evasion strategies. Nat. Rev. Immunol. 9, 503–513 (2009).
Google Scholar
Maguire, C. et al. Molecular mimicry as a mechanism of viral immune evasion and autoimmunity. Nat. Commun. 15, 9403 (2024).
Google Scholar
Ma, Z. & Damania, B. The cGAS-STING defense pathway and its counteraction by viruses. Cell Host Microbe 19, 150–158 (2016).
Google Scholar
Locatelli, M. & Faure-Dupuy, S. Virus hijacking of host epigenetic machinery to impair immune response. J. Virol. 97, e0065823 (2023).
Google Scholar
Huang, Z. M. et al. Decoy receptor 3 suppresses TLR2-mediated B cell activation by targeting NF-κB. J. Immunol. 188, 5867–5876 (2012).
Google Scholar
Katzourakis, A. & Gifford, R. J. Endogenous viral elements in animal genomes. PLoS Genet. 6, e1001191 (2010).
Google Scholar
Liang, G. & Bushman, F. D. The human virome: assembly, composition and host interactions. Nat. Rev. Microbiol. 19, 514–527 (2021). A comprehensive review of human virome composition and host interactions, providing an essential reference for the full scope of virome complexity.
Google Scholar
Van Blerkom, L. M. Role of viruses in human evolution. Am. J. Phys. Anthropol. 37, 14–46 (2003).
Google Scholar
Virgin, H. W., Wherry, E. J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009).
Google Scholar
Quintana-Murci, L. & Clark, A. G. Population genetic tools for dissecting innate immunity in humans. Nat. Rev. Immunol. 13, 280–293 (2013).
Google Scholar
Kassiotis, G. & Stoye, J. P. Immune responses to endogenous retroelements: taking the bad with the good. Nat. Rev. Immunol. 16, 207–219 (2016).
Google Scholar
Mi, S. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403, 785–789 (2000). This study showed that a protein essential for human placental morphogenesis is derived from a retroviral envelope gene, providing an early example how ERVs have been co-opted for indispensable host physiological functions.
Google Scholar
Ashley, J. et al. Retrovirus-like gag protein arc1 binds RNA and traffics across synaptic boutons. Cell 172, 262–274 e211 (2018).
Google Scholar
Pastuzyn, E. D. et al. The neuronal gene Arc encodes a repurposed retrotransposon gag protein that mediates intercellular RNA transfer. Cell 173, 275 (2018).
Google Scholar
Segel, M. et al. Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery. Science 373, 882–889 (2021).
Google Scholar
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory activities of transposable elements: from conflicts to benefits. Nat. Rev. Genet. 18, 71–86 (2017).
Google Scholar
Thompson, P. J., Macfarlan, T. S. & Lorincz, M. C. Long terminal repeats: from parasitic elements to building blocks of the transcriptional regulatory repertoire. Mol. Cell 62, 766–776 (2016).
Google Scholar
Cohen, C. J., Lock, W. M. & Mager, D. L. Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene 448, 105–114 (2009).
Google Scholar
Kunarso, G. et al. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat. Genet. 42, 631–634 (2010).
Google Scholar
Lecuit, M. & Eloit, M. The human virome: new tools and concepts. Trends Microbiol. 21, 510–515 (2013).
Google Scholar
Luri-Rey, C. et al. Cross-priming in cancer immunology and immunotherapy. Nat. Rev. Cancer 25, 249–273 (2025).
Google Scholar
Lopez-Verges, S. et al. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc. Natl Acad. Sci. USA 108, 14725–14732 (2011).
Google Scholar
Beziat, V. et al. CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur. J. Immunol. 42, 447–457 (2012).
Google Scholar
Schlums, H. et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443–456 (2015).
Google Scholar
Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005).
Google Scholar
Krug, A. et al. Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 103, 1433–1437 (2004).
Google Scholar
Hochrein, H. et al. Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 101, 11416–11421 (2004).
Google Scholar
Madera, S. et al. Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J. Exp. Med. 213, 225–233 (2016).
Google Scholar
Lee, A. J. et al. Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection. J. Exp. Med. 214, 1153–1167 (2017).
Google Scholar
Hwee, J. et al. A systematic review and meta-analysis of the association between childhood infections and the risk of childhood acute lymphoblastic leukaemia. Br. J. Cancer 118, 127–137 (2018).
Google Scholar
Becker, N. et al. Self-reported history of infections and the risk of non-Hodgkin lymphoma: an InterLymph pooled analysis. Int. J. Cancer 131, 2342–2348 (2012).
Google Scholar
Wrensch, M. et al. Does prior infection with varicella-zoster virus influence risk of adult glioma? Am. J. Epidemiol. 145, 594–597 (1997).
Google Scholar
Chen, Y. et al. Rhinovirus induces airway epithelial gene expression through double-stranded RNA and IFN-dependent pathways. Am. J. Respir. Cell Mol. Biol. 34, 192–203 (2006).
Google Scholar
Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).
Google Scholar
Selin, L. K., Varga, S. M., Wong, I. C. & Welsh, R. M. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J. Exp. Med. 188, 1705–1715 (1998).
Google Scholar
Grippin, A. J. et al. SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. Nature 647, 488–497 (2025). This study demonstrated that SARS-CoV-2 mRNA vaccination sensitizes tumors to ICB, connecting vaccine-induced antiviral immunity to the enhancement of cancer immunotherapy.
Google Scholar
Kong, Y. et al. Transposable element expression in tumors is associated with immune infiltration and increased antigenicity. Nat. Commun. 10, 5228 (2019).
Google Scholar
Elde, N. C. & Malik, H. S. The evolutionary conundrum of pathogen mimicry. Nat. Rev. Microbiol. 7, 787–797 (2009).
Google Scholar
Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013).
Google Scholar
Lanz, T. V. et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 603, 321–327 (2022).
Google Scholar
Chiaro, J. et al. Viral molecular mimicry influences the antitumor immune response in murine and human melanoma. Cancer Immunol. Res. 9, 981–993 (2021). This study provides direct experimental evidence that viral molecular mimicry shapes the antitumour immune response in both mouse and human melanoma.
Google Scholar
Chiou, S. H. et al. Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery. Immunity 54, 586–602 e588 (2021).
Google Scholar
Manolio, C. et al. Antigenic molecular mimicry in viral-mediated protection from cancer: the HIV case. J. Transl. Med. 20, 472 (2022).
Google Scholar
Ragone, C. et al. Molecular mimicry of SARS-COV-2 antigens as a possible natural anti-cancer preventive immunization. Front. Immunol. 15, 1398002 (2024).
Google Scholar
Smith, C. M. et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat. Immunol. 5, 1143–1148 (2004).
Google Scholar
Ahrends, T. et al. CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities. Nat. Commun. 10, 5531 (2019).
Google Scholar
English, K. et al. A hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs. Nat. Commun. 15, 1261 (2024).
Google Scholar
Borst, J., Ahrends, T., Babala, N., Melief, C. J. M. & Kastenmuller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 18, 635–647 (2018).
Google Scholar
Campa, M. J., Gottlin, E. B., Wiehe, K. & Patz, E. F. Jr. A tumor-binding antibody with cross-reactivity to viral antigens. Cancer Immunol. Immunother. 74, 126 (2025).
Google Scholar
Hung, M. H. et al. Enteroviral epitope mimicry enables NK cell-mediated targeting of ASPH in hepatocellular carcinoma. Preprint at bioRxiv https://doi.org/10.64898/2026.04.07.717032 (2026). A preprint showing that enteroviral epitope mimicry enables natural killer cell-mediated targeting of the tumour antigen ASPH in HCC.
Ma, L. et al. Beneficial infections of the enterovirus genus in patients with liver cancer. Gut 74, 1667–1679 (2025). The key primary paper underlying this Review’s central thesis, demonstrating that enterovirus exposure is associated with protective antitumour immunity in patients with liver cancer and identifying a specific mechanism based on a cross-reactive epitope.
Google Scholar
Kalaora, S. et al. Identification of bacteria-derived HLA-bound peptides in melanoma. Nature 592, 138–143 (2021).
Google Scholar
Naghavian, R. et al. Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma. Nature 617, 807–817 (2023).
Google Scholar
Levitskaya, J. et al. Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature 375, 685–688 (1995).
Google Scholar
Fang, W. et al. EBV-driven LMP1 and IFN-gamma up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy. Oncotarget 5, 12189–12202 (2014).
Google Scholar
Liu, C. et al. Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity. Mol. Med. Rep. 15, 1063–1070 (2017).
Google Scholar
Chen, J. et al. Expression of PD-1 and PD-Ls in Kaposi’s sarcoma and regulation by oncogenic herpesvirus lytic reactivation. Virology 536, 16–19 (2019).
Google Scholar
Host, K. M. et al. Kaposi’s sarcoma-associated herpesvirus increases PD-L1 and proinflammatory cytokine expression in human monocytes. mBio 8, e00917–e00917 (2017).
Google Scholar
Ishido, S., Wang, C., Lee, B. S., Cohen, G. B. & Jung, J. U. Downregulation of major histocompatibility complex class I molecules by Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. J. Virol. 74, 5300–5309 (2000).
Google Scholar
Story, C. M., Furman, M. H. & Ploegh, H. L. The cytosolic tail of class I MHC heavy chain is required for its dislocation by the human cytomegalovirus US2 and US11 gene products. Proc. Natl Acad. Sci. USA 96, 8516–8521 (1999).
Google Scholar
Wiertz, E. J. et al. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84, 769–779 (1996).
Google Scholar
Yuan, Q. et al. Human cytomegalovirus UL23 exploits PD-L1 inhibitory signaling pathway to evade T cell-mediated cytotoxicity. mBio 15, e0119124 (2024).
Google Scholar
Meier, A. et al. Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands. AIDS 22, 655–658 (2008).
Google Scholar
Planes, R. et al. HIV-1 Tat protein induces PD-L1 (B7-H1) expression on dendritic cells through tumor necrosis factor alpha- and toll-like receptor 4-mediated mechanisms. J. Virol. 88, 6672–6689 (2014).
Google Scholar
Muthumani, K. et al. Human immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism. J. Virol. 82, 11536–11544 (2008).
Google Scholar
Galocha, B. et al. The active site of ICP47, a herpes simplex virus-encoded inhibitor of the major histocompatibility complex (MHC)-encoded peptide transporter associated with antigen processing (TAP), maps to the NH2-terminal 35 residues. J. Exp. Med. 185, 1565–1572 (1997).
Google Scholar
Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).
Google Scholar
Radziewicz, H. et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J. Virol. 81, 2545–2553 (2007).
Google Scholar
Urbani, S. et al. Restoration of HCV-specific T cell functions by PD-1/PD-L1 blockade in HCV infection: effect of viremia levels and antiviral treatment. J. Hepatol. 48, 548–558 (2008).
Google Scholar
Fisicaro, P. et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 138, 682–693 (2010).
Google Scholar
Rice, A. E. et al. An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression. Cancer Gene Ther. 22, 454–462 (2015).
Google Scholar
West, E. E. et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Invest. 123, 2604–2615 (2013).
Google Scholar
Chumakov, P. M. et al. Oncolytic enteroviruses. Mol. Biol. 46, 712–725 (2012).
Google Scholar
Voroshilova, M. K. Potential use of nonpathogenic enteroviruses for control of human disease. Prog. Med. Virol. 36, 191–202 (1989). An early study of the potential for non-pathogenic enteroviruses to control human disease, enlightening oncolytic virotherapy using naturally occurring enteroviruses.
Google Scholar
Liu, J. et al. A viral exposure signature defines early onset of hepatocellular carcinoma. Cell 182, 317–328 e310 (2020). This study used comprehensive viral exposure profiling to identify a virome signature that predicts early-onset HCC, demonstrating that systematic virome serology can serve as a cancer risk biomarker.
Google Scholar
Do, W. L. et al. Pan-viral serology uncovers distinct virome patterns as risk predictors of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cell Rep. Med. 4, 12 (2023).
Xu, G. J. et al. Viral immunology. comprehensive serological profiling of human populations using a synthetic human virome. Science 348, aaa0698 (2015).
Google Scholar
Palmenberg, A. C. & Gern, J. E. in Rhinoviruses 1–10 (Springer, 2015).
Heikkinen, T. & Jarvinen, A. The common cold. Lancet 361, 51–59 (2003).
Google Scholar
Tran, C. B. et al. The seroprevalence and seroincidence of enterovirus71 infection in infants and children in Ho Chi Minh City, Viet Nam. PLoS ONE 6, e21116 (2011).
Google Scholar
Fall, A. et al. Global prevalence and case fatality rate of enterovirus D68 infections, a systematic review and meta-analysis. PLoS Negl. Trop. Dis. 16, e0010073 (2022).
Google Scholar
Bhattacharjee, A. et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc. Natl Acad. Sci. USA 98, 13790–13795 (2001).
Google Scholar
Pyeon, D., Vu, L., Giacobbi, N. S. & Westrich, J. A. The antiviral immune forces awaken in the cancer wars. PLoS Pathog. 16, e1008814 (2020).
Google Scholar
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015). This study showed that DNA demethylation in cancer cells de-represses ERVs and triggers an interferon response that resensitizes tumours to immunity.
Google Scholar
Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).
Google Scholar
Natoli, M. et al. Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression. J. Immunother. Cancer 9, e001519 (2021).
Google Scholar
Golkaram, M. et al. HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome. npj Genom. Med. 6, 13 (2021).
Google Scholar
Schiavetti, F., Thonnard, J., Colau, D., Boon, T. & Coulie, P. G. A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes. Cancer Res. 62, 5510–5516 (2002).
Google Scholar
Cherkasova, E. et al. Detection of an immunogenic HERV-E envelope with selective expression in clear cell kidney cancer. Cancer Res. 76, 2177–2185 (2016).
Google Scholar
Wang-Johanning, F. et al. Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res. 68, 5869–5877 (2008).
Google Scholar
Wang-Johanning, F. et al. Expression of multiple human endogenous retrovirus surface envelope proteins in ovarian cancer. Int. J. Cancer 120, 81–90 (2007).
Google Scholar
Cañadas, I. et al. Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat. Med. 24, 1143–1150 (2018). This study demonstrated that specific interferon-stimulated ERVs can prime innate immunity against tumours, providing evidence that ERV expression drives antitumour immune responses.
Google Scholar
Russell, S. J., Peng, K. W. & Bell, J. C. Oncolytic virotherapy. Nat. Biotechnol. 30, 658–670 (2012).
Google Scholar
Harrington, K., Freeman, D. J., Kelly, B., Harper, J. & Soria, J. C. Optimizing oncolytic virotherapy in cancer treatment. Nat. Rev. Drug Discov. 18, 689–706 (2019).
Google Scholar
Norman, K. L., Hirasawa, K., Yang, A. D., Shields, M. A. & Lee, P. W. Reovirus oncolysis: the Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection. Proc. Natl Acad. Sci. USA 101, 11099–11104 (2004).
Google Scholar
Coffey, M. C., Strong, J. E., Forsyth, P. A. & Lee, P. W. Reovirus therapy of tumors with activated Ras pathway. Science 282, 1332–1334 (1998).
Google Scholar
Vidal, L. et al. A phase I study of intravenous oncolytic reovirus type 3 Dearing in patients with advanced cancer. Clin. Cancer Res. 14, 7127–7137 (2008).
Google Scholar
Forsyth, P. et al. A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas. Mol. Ther. 16, 627–632 (2008).
Google Scholar
Harrington, K. J. et al. Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers. Clin. Cancer Res. 16, 3067–3077 (2010).
Google Scholar
Mahalingam, D. et al. Pembrolizumab in combination with the oncolytic virus pelareorep and chemotherapy in patients with advanced pancreatic adenocarcinoma: a phase Ib study. Clin. Cancer Res. 26, 71–81 (2020).
Google Scholar
Andtbacka, R. H. I. et al. Clinical responses of oncolytic coxsackievirus A21 (V937) in patients with unresectable melanoma. J. Clin. Oncol. 39, 3829–3838 (2021).
Google Scholar
Pecora, A. L. et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J. Clin. Oncol. 20, 2251–2266 (2002).
Google Scholar
Geletneky, K. et al. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol. Ther. 25, 2620–2634 (2017).
Google Scholar
Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015). The landmark phase III trial of talimogene laherparepvec (T-VEC), which led to the first FDA-approved oncolytic virus therapy for advanced melanoma and validating this therapeutic approach.
Google Scholar
Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19, 329–336 (2013).
Google Scholar
Desjardins, A. et al. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 379, 150–161 (2018).
Google Scholar
Russell, S. J. et al. Remission of disseminated cancer after systemic oncolytic virotherapy. Mayo Clin. Proc. 89, 926–933 (2014).
Google Scholar
Smith, K. E. R. et al. A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses. Front. Immunol. 14, 1279387 (2023).
Google Scholar
Khuri, F. R. et al. a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat. Med. 6, 879–885 (2000).
Google Scholar
Sepich-Poore, G. D. et al. The microbiome and human cancer. Science 371, eabc4552 (2021).
Google Scholar
Belkaid, Y. & Harrison, O. J. Homeostatic immunity and the microbiota. Immunity 46, 562–576 (2017).
Google Scholar
Barr, J. J. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl Acad. Sci. USA 110, 10771–10776 (2013).
Google Scholar
Nguyen, S. et al. Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers. mBio 8, e01874–17 (2017).
Google Scholar
Gogokhia, L. et al. Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis. Cell Host Microbe 25, 285–299 e288 (2019).
Google Scholar
Federici, S. et al. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell 185, 2879–2898 e2824 (2022).
Google Scholar
Ichikawa, M. et al. Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis. Nat. Commun. 14, 3261 (2023).
Google Scholar
de Haas, C. J. et al. Chemotaxis inhibitory protein of Staphylococcus aureus, a bacterial antiinflammatory agent. J. Exp. Med. 199, 687–695 (2004).
Google Scholar
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Google Scholar
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Google Scholar
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Google Scholar
Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).
Google Scholar
Mar, J. S. et al. IL-22 alters gut microbiota composition and function to increase aryl hydrocarbon receptor activity in mice and humans. Microbiome 11, 47 (2023).
Google Scholar
Steed, A. L. et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357, 498–502 (2017).
Google Scholar
Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).
Google Scholar
Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). Along with Sivan et al. (2015), this study demonstrates that the gut microbiome is required for the efficacy of ICB therapy, establishing the microbiome as a major determinant of therapy outcome.
Google Scholar
Federici, S., Nobs, S. P. & Elinav, E. Phages and their potential to modulate the microbiome and immunity. Cell Mol. Immunol. 18, 889–904 (2021).
Google Scholar
Kumata, R., Ito, J., Takahashi, K., Suzuki, T. & Sato, K. A tissue level atlas of the healthy human virome. BMC Biol. 18, 55 (2020).
Google Scholar
Bigley, A. B. et al. Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans. Clin. Exp. immunol. 185, 239–251 (2016). This study provides direct evidence that a common persistent virus can enhance immune surveillance against cancer in humans.
Google Scholar
Montella, M. et al. Do childhood diseases affect NHL and HL risk? A case–control study from northern and southern Italy. Leuk. Res. 30, 917–922 (2006).
Google Scholar
Strickley, J. D. et al. Immunity to commensal papillomaviruses protects against skin cancer. Nature 575, 519–522 (2019).
Google Scholar
Son, H. G. et al. Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin. Cancer Cell 43, 36–48 e10 (2025).
Google Scholar
Jager, E. et al. Identification of NY-ESO-1 epitopes presented by human histocompatibility antigen (HLA)-DRB4*0101-0103 and recognized by CD4+ T lymphocytes of patients with NY-ESO-1-expressing melanoma. J. Exp. Med. 191, 625–630 (2000).
Google Scholar
Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).
Google Scholar
Robbins, P. F. et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).
Google Scholar
Odunsi, K. et al. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Proc. Natl Acad. Sci. USA 104, 12837–12842 (2007).
Google Scholar
Jager, E. et al. Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. Proc. Natl Acad. Sci. USA 97, 12198–12203 (2000).
Google Scholar
Feuchtinger, T. et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 116, 4360–4367 (2010).
Google Scholar
Paston, S. J., Dodi, I. A. & Madrigal, J. A. Progress made towards the development of a CMV peptide vaccine. Hum. Immunol. 65, 544–549 (2004).
Google Scholar
Thompson, E. M. et al. A peptide vaccine targeting the CMV antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma: a phase 1 trial. Nat. Cancer 6, 1559–1569 (2025).
Google Scholar
Prockop, S. E. et al. Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant. J. Clin. Invest. 133, e165476 (2023).
Google Scholar
Mohan, D. et al. PhIP-seq characterization of serum antibodies using oligonucleotide-encoded peptidomes. Nat. Protoc. 13, 1958–1978 (2018).
Google Scholar
Bourgonje, A. R. et al. Phage-display immunoprecipitation sequencing of the antibody epitope repertoire in inflammatory bowel disease reveals distinct antibody signatures. Immunity 56, 1393–1409 e1396 (2023).
Google Scholar
Andreu-Sanchez, S. et al. Phage display sequencing reveals that genetic, environmental, and intrinsic factors influence variation of human antibody epitope repertoire. Immunity 56, 1376–1392 e1378 (2023).
Google Scholar
Mina, M. J. et al. Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science 366, 599–606 (2019).
Google Scholar
Mentzer, A. J. et al. Identification of host-pathogen-disease relationships using a scalable multiplex serology platform in UK Biobank. Nat. Commun. 13, 1818 (2022).
Google Scholar
Robbins, H. A. et al. Absolute risk of oropharyngeal cancer after an HPV16-E6 serology test and potential implications for screening: results from the human papillomavirus cancer cohort consortium. J. Clin. Oncol. 40, 3613–3622 (2022).
Google Scholar
Paudel, S. et al. Serologic profiling using an epstein-barr virus mammalian expression library identifies EBNA1 IgA as a prediagnostic marker for nasopharyngeal carcinoma. Clin. Cancer Res. 28, 5221–5230 (2022).
Google Scholar
Ji, M. F. et al. Epstein Barr virus antibody and cancer risk in two prospective cohorts in Southern China. Nat. Commun. 16, 5940 (2025).
Google Scholar
Yang, H. I. et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N. Engl. J. Med. 347, 168–174 (2002).
Google Scholar
Arisaw, K. et al. A nested case–control study of risk factors for adult T-cell leukemia/lymphoma among human T-cell lymphotropic virus type-I carriers in Japan. Cancer Causes Control 13, 657–663 (2002).
Google Scholar
Gao, S. J. et al. Seroconversion to antibodies against Kaposi’s sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi’s sarcoma. N. Engl. J. Med. 335, 233–241 (1996).
Google Scholar
Amirian, E. S., Marquez-Do, D., Bondy, M. L. & Scheurer, M. E. Anti-human-cytomegalovirus immunoglobulin G levels in glioma risk and prognosis. Cancer Med. 2, 57–62 (2013).
Google Scholar
Coghill, A. E. et al. Prospective investigation of herpesvirus infection and risk of glioma. Int. J. Cancer 151, 222–228 (2022).
Google Scholar
Chan, K. C. A. et al. Analysis of plasma Epstein-Barr Virus DNA to screen for nasopharyngeal cancer. N. Engl. J. Med. 377, 513–522 (2017). The key clinical translation paper for EBV-based screening for nasopharyngeal cancer.
Google Scholar
Miller, J. A., Le, Q. T., Pinsky, B. A. & Wang, H. Cost-effectiveness of nasopharyngeal carcinoma screening with Epstein–Barr virus polymerase chain reaction or serology in high-incidence populations worldwide. J. Natl Cancer Inst. 113, 852–862 (2021).
Google Scholar
Sankaranarayanan, R. et al. HPV screening for cervical cancer in rural India. N. Engl. J. Med. 360, 1385–1394 (2009).
Google Scholar
Zhao, F. H. et al. An evaluation of novel, lower-cost molecular screening tests for human papillomavirus in rural China. Cancer Prev. Res. 6, 938–948 (2013).
Google Scholar
Lazcano-Ponce, E. et al. Specimen self-collection and HPV DNA screening in a pilot study of 100,242 women. Int. J. Cancer 135, 109–116 (2014).
Google Scholar
Barnabas, R. V. et al. Durability of single-dose HPV vaccination in young Kenyan women: randomized controlled trial 3-year results. Nat. Med. 29, 3224–3232 (2023).
Google Scholar
Hannigan, G. D., Duhaime, M. B., Ruffin, M. T. T., Koumpouras, C. C. & Schloss, P. D. Diagnostic potential and interactive dynamics of the colorectal cancer virome. mBio 9, e02248-18 (2018).
Google Scholar
Hsu, C. L. et al. Viral antibody response predicts morbidity and mortality in alcohol-associated hepatitis. Hepatology 82, 127–139 (2025).
Google Scholar
Lipsick, J. A history of cancer research: tumor viruses. Cold Spring Harb. Perspect. Biol. 13, a035774 (2021).
Google Scholar
Wu, T.-C., Chang, M. H. & Jeang, K.-T. (eds) Viruses and Human Cancer: From Basic Science to Clinical Prevention 2nd edn (Springer, 2021).
Rous, P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 13, 397–411 (1911). The foundational study for the field of tumour virology, demonstrating that a filterable agent — later identified as a retrovirus — could transmit sarcoma between chickens.
Google Scholar
Javier, R. T. & Butel, J. S. The history of tumor virology. Cancer Res. 68, 7693–7706 (2008).
Google Scholar
Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976). This study identified normal cellular homologues of the transforming genes that avian sarcoma viruses have, establishing the concept of proto-oncogenes and the connection between virology and cancer cell biology, winning the authors a Nobel Prize.
Google Scholar
Parada, L. F., Tabin, C. J., Shih, C. & Weinberg, R. A. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus Ras gene. Nature 297, 474–478 (1982).
Google Scholar
Downward, J. et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307, 521–527 (1984).
Google Scholar
Bishop, J. M. Enemies within: the genesis of retrovirus oncogenes. Cell 23, 5–6 (1981).
Google Scholar
Vogt, P. K. Retroviral oncogenes: a historical primer. Nat. Rev. Cancer 12, 639–648 (2012).
Google Scholar
Durst, M., Gissmann, L., Ikenberg, H. & zur Hausen, H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc. Natl Acad. Sci. USA 80, 3812–3815 (1983). This study identified HPV DNA in cervical carcinoma and demonstrated its geographical prevalence in cancer biopsies, an experimental breakthrough, which led to Harald zur Hausen being awarded the Nobel Prize and the subsequent development of HPV vaccines.
Google Scholar
Munoz, N., Castellsague, X., Berrington de Gonzalez, A. & Gissmann, L. Chapter 1: HPV in the etiology of human cancer. Vaccine 24, S3/1–S3/10 (2006).
Google Scholar
Vousden, K. H. Human papillomavirus oncoproteins. Semin. Cancer Biol. 1, 415–424 (1990).
Google Scholar
Alcami, A. & Koszinowski, U. H. Viral mechanisms of immune evasion. Trends Microbiol. 8, 410–418 (2000).
Google Scholar
Qian, W. et al. Respiratory viral infections prime accelerated lung cancer growth. Cell 189, 2845–2856.e20 (2026).
Google Scholar
