When cancer is discussed, it is usually associated with genetic mutations, environmental factors, or lifestyle habits such as smoking or diet. However, for several decades it has been known that some viruses play a fundamental role in the development of certain types of human cancer.
These viruses, known as oncoviruses, represent a major global public health issue and are estimated to be involved in approximately 20% of all cancer cases worldwide. Understanding how these infectious agents act has not only deepened our knowledge of carcinogenesis but has also enabled the development of innovative preventive and therapeutic strategies.
Oncoviruses are viruses capable of inducing malignant transformation as a consequence of persistent infection. Unlike acute viral infections that are rapidly cleared, these infections can persist for years or even decades within the host. During this time, viruses continuously interact with host cells, altering essential cellular processes and creating an environment conducive to the accumulation of genetic and epigenetic damage.
Currently, seven viruses are firmly established as human oncoviruses: human papillomavirus (HPV), Epstein–Barr virus (EBV), hepatitis B and C viruses (HBV and HCV), human T-cell lymphotropic virus type 1 (HTLV-1), Kaposi’s sarcoma–associated herpesvirus (KSHV), and Merkel cell polyomavirus (MCPyV).
Figure 1. Major human oncoviruses and the types of cancer with which they are associated. This includes well-established viruses such as HPV, EBV, HBV/HCV, HTLV-1, KSHV, and MCPyV, highlighting their involvement in different carcinogenic processes and in the development of human malignancies.
Although these viruses differ in structure, genome organization, and life cycle, they share common mechanisms that explain their oncogenic potential. One of the most important is the inactivation of tumor suppressor genes.
Specific viral proteins can interfere with critical cellular proteins such as p53 and retinoblastoma (Rb), which normally function as guardians of the genome by halting abnormal cell proliferation or inducing cell death when DNA damage is detected.
By blocking these control pathways, infected cells can divide without restriction, increasing the risk of malignant transformation.
In addition to disrupting cell cycle control mechanisms, many oncoviruses promote a state of chronic inflammation. Persistent inflammation generates a microenvironment rich in cytokines, reactive oxygen species, and growth signals that favor DNA damage and the survival of altered cells.
This is compounded by the ability of some viruses to induce genomic instability and epigenetic changes, such as alterations in DNA methylation or gene expression regulation, further contributing to tumor progression.
Human papillomavirus
Is one of the clearest and best-studied examples of viral carcinogenesis. Certain high-risk types, particularly HPV16 and HPV18, are directly linked to cervical cancer as well as other anogenital and oropharyngeal cancers.
The viral proteins E6 and E7 play a central role by inactivating p53 and Rb, eliminating key barriers to uncontrolled cell proliferation. The development of prophylactic vaccines against HPV has proven to be one of the most successful strategies in cancer prevention, significantly reducing cancer incidence in vaccinated populations.
Hepatitis B and C viruses
Provide another important example of oncoviruses with a major public health impact. Both are closely associated with hepatocellular carcinoma, one of the most common and deadly cancers worldwide.
In these cases, viral carcinogenesis is strongly linked to chronic liver inflammation, fibrosis, and cirrhosis. HBV can integrate its DNA into the host cell genome, potentially disrupting critical cellular genes, while HCV induces oxidative stress and alters multiple intracellular signaling pathways.
Over time, these cumulative alterations create an environment favorable to liver cancer development.
Epstein–Barr virus
Is one of the most common human viruses and infects the majority of the global population, typically during childhood or adolescence. Although infection is usually asymptomatic and remains latent, EBV is associated with several cancers, including lymphomas, nasopharyngeal carcinoma, and certain gastric cancers.
Proteins expressed during viral latency allow infected cells to evade apoptosis, modulate immune responses, and maintain survival signals, which under specific conditions can lead to malignant transformation.
HTLV-1
Is a retrovirus with an exceptionally long latency period, often extending for decades before disease onset. It is associated with adult T-cell leukemia/lymphoma, a highly aggressive malignancy. Viral proteins such as Tax and HBZ activate oncogenic pathways, disrupt cell cycle regulation, and contribute to immune evasion, facilitating the expansion of infected cells with malignant potential.
KSHV and MCPyV
Are considered emerging but clinically significant. KSHV is responsible for Kaposi’s sarcoma and certain lymphomas, particularly in immunocompromised individuals. This virus encodes multiple proteins and microRNAs that promote angiogenesis, inflammation, and resistance to apoptosis. MCPyV, on the other hand, is associated with Merkel cell carcinoma, a rare but highly aggressive skin cancer, in which the virus is often clonally integrated into the genome of tumor cells.
Figure 2. Infection with oncogenic viruses such as HPV, HBV, or EBV can lead to viral genome integration and chronic infection, promoting cellular transformation. This process may result in precancerous changes that progress to cancer through genomic instability and loss of tumor suppressor genes, while in some cases triggering apoptosis as an alternative outcome.
The study of oncoviruses has had profound clinical implications. The development of vaccines, antiviral therapies, immunotherapy approaches, and innovative strategies such as oncolytic virotherapy has been made possible by a deeper understanding of viral carcinogenesis. In addition, the identification of viral biomarkers has improved diagnosis, prognosis, and the selection of personalized treatments for patients.
As research continues to advance, new strategies are expected to more precisely block interactions between oncogenic viruses and human cells. The integration of virology, immunology, and oncology is transforming how cancer is understood—not only as a genetic disease, but also as the result of complex interactions between persistent infections and the host. Understanding and combating oncoviruses not only offers new therapeutic opportunities but also opens the door to effective cancer prevention before the disease develops.
Main reference:
Warowicka, A., Nawrot, R., Broniarczyk, J., Węglewska, M., & Goździcka-Józefiak, A. (2021). Wirusy onkogenne a nowotwory [Oncogenic viruses and cancer]. Postepy biochemii, 66(4), 336–355. https://doi.org/10.18388/pb.2020_360
Other reference:
Mui, U. N., Haley, C. T., & Tyring, S. K. (2017). Viral Oncology: Molecular Biology and Pathogenesis. Journal of clinical medicine, 6(12), 111. https://doi.org/10.3390/jcm6120111
Chang, Y., Moore, P. S., & Weiss, R. A. (2017). Human oncogenic viruses: nature and discovery. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 372(1732), 20160264. https://doi.org/10.1098/rstb.2016.0264
Schiller, J. T., & Lowy, D. R. (2014). Virus infection and human cancer: an overview. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer, 193, 1–10. https://doi.org/10.1007/978-3-642-38965-8_1
