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Cytomegalovirus and Cancer: Revisiting Oncogenic Hypotheses and Therapeutic Perspectives

  † These authors contributed equally to this work.

Submitted:

05 November 2025

Posted:

07 November 2025

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Abstract
Human cytomegalovirus (HCMV) has emerged as a potential oncomodulatory agent implicated in the pathogenesis of several cancers, although its precise role in tumorigenesis remains a subject of debate. This review synthesizes five decades of research examining the involvement of HCMV in cancer, with particular focus on molecular mechanisms by which the virus may contribute to tumor progression, including immune evasion, chronic inflammation, and modulation of cell cycle and signaling pathways. Evidence of HCMV detection in malignancies such as glioblastoma, breast, colorectal, and prostate cancers is critically reviewed, alongside ongoing controversies regarding its causal versus passenger role in oncogenesis.The review further explores current and emerging antiviral and immunotherapeutic strategies targeting HCMV within oncological settings, highlighting their potential translational relevance and associated challenges. By reassessing oncogenic hypotheses and therapeutic opportunities, this article aims to provide a comprehensive perspective on the complex interplay between HCMV and cancer biology, and to evaluate its potential as a novel target for cancer prevention and therapy.
Keywords: 
cytomegalovirus
;  
cancer
;  
viral oncogenesis
;  
glioblastoma
;  
antiviral therapy
;  
oncomodulation
Subject: 
Biology and Life Sciences  -   Virology

Introduction

Cancer is a multifaceted disease characterized by the uncontrolled proliferation of cells and their capacity to invade neighboring tissues and metastasize to distant sites [1]. Despite decades of research, cancer remains a leading cause of mortality worldwide, underscoring the complexity of its etiology and pathogenesis. The causes of cancer are multifactorial, involving genetic mutations, environmental exposures such as tobacco and radiation, lifestyle factors, and biological agents [2]. Among biological contributors, infectious agents, particularly oncogenic viruses, have been increasingly recognized as significant drivers in the initiation and progression of various malignancies [3]. Viruses are estimated to contribute to approximately 15–20% of human cancers globally, exerting their effects through diverse mechanisms including direct oncogene expression and chronic inflammation [4].
Human cytomegalovirus (HCMV), a member of the Herpesviridae family, infects a majority of the human population worldwide and establishes lifelong latency after primary infection [5]. Traditionally, CMV has been studied in the context of congenital infections and opportunistic disease in immunocompromised patients. However, emerging evidence over the past five decades suggests CMV’s potential role in oncogenesis or as an oncomodulatory agent in various cancers. CMV DNA, RNA, and proteins have been detected in multiple tumor types, suggesting a possible contributory role in cancer biology [6,7,8]. This review aims to synthesize current knowledge on CMV’s relationship with cancer, revisit oncogenic hypotheses, explore therapeutic implications, and highlight future research directions.

Biological Causes of Cancer: Viral Oncogenesis

The discovery that viruses can cause cancer revolutionized our understanding of oncogenesis. Several viruses have been firmly established as carcinogens, including human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B and C viruses (HBV, HCV), and human T-cell lymphotropic virus type 1 (HTLV-1) [9]. These viruses induce malignancy by integrating their genetic material into host cells, producing oncogenic proteins, and modulating cellular pathways that govern proliferation, apoptosis, and immune evasion [10].
For example, HPV induces cervical and other anogenital cancers through the E6 and E7 proteins, which inactivate tumor suppressor proteins p53 and retinoblastoma (Rb), leading to uncontrolled cell division [11]. EBV’s latent membrane proteins promote B-cell transformation and contribute to lymphomas and nasopharyngeal carcinoma [12]. Chronic HBV and HCV infections induce liver inflammation and cirrhosis, creating a microenvironment conducive to hepatocellular carcinoma [13]. HTLV-1 encodes Tax, a transactivator that disrupts cell cycle checkpoints, promoting adult T-cell leukemia [14].
Beyond direct oncogene expression, chronic viral infections can cause persistent inflammation, DNA damage, and immune dysregulation, all contributing to a pro-carcinogenic environment [15]. Viral latency and reactivation can further contribute to genomic instability. Understanding viral oncogenesis has not only deepened insights into cancer biology but has also paved the way for virus-targeted therapies and vaccines.

Human Cytomegalovirus (HCMV): Virology and Pathobiology

Human cytomegalovirus is a double-stranded DNA virus classified in the beta-herpesvirus subfamily, characterized by its ability to establish lifelong latency after primary infection [16]. CMV infects a broad range of cell types, including epithelial cells, endothelial cells, fibroblasts, smooth muscle cells, and myeloid progenitors [17]. Primary infection is usually asymptomatic in immunocompetent individuals but can be severe in immunocompromised patients and neonates [18].
CMV establishes latency mainly in myeloid progenitor cells in the bone marrow and can reactivate under conditions of immunosuppression, stress, or inflammation [19]. Its genome encodes more than 200 proteins, many of which modulate host immune responses by downregulating major histocompatibility complex (MHC) molecules, interfering with cytokine signaling, and evading natural killer cell detection [20]. This immune evasion is critical for viral persistence and may also facilitate tumor immune escape mechanisms.
The global seroprevalence of CMV infection varies widely, ranging from 40% to nearly 100% depending on geographic region and socioeconomic factors [21]. Given its high prevalence and lifelong persistence, CMV infection represents a significant factor to consider in the etiology of diseases beyond classical viral syndromes.

Evidence Linking CMV to Cancer

The potential involvement of CMV in cancer was first suggested by the detection of CMV nucleic acids and proteins in various tumor tissues [22]. CMV presence has been reported in several cancer types, with varying degrees of detection and clinical significance (Table 1). Glioblastoma multiforme (GBM), a highly aggressive brain tumor, has been extensively studied with consistent detection of CMV DNA and proteins in tumor cells but rarely in adjacent normal tissue [23]. Other solid tumors such as breast cancer, colorectal cancer, prostate cancer, and medulloblastoma have also demonstrated CMV components within tumor cells, raising the hypothesis that CMV infection may influence tumor biology [24,25,26,27].
Studies have shown that CMV gene products are expressed in tumor cells, suggesting active viral gene expression rather than latent infection or contamination [28]. Importantly, the localization of CMV in malignant but not normal tissues argues for a role beyond a passive bystander. Experimental infection of cultured cells with CMV has been shown to induce phenotypic changes relevant to cancer, including enhanced proliferation, increased invasiveness, resistance to apoptosis, and promotion of angiogenesis [29].
Nonetheless, the question remains whether CMV plays a causative role in tumorigenesis or acts as an oncomodulator that facilitates cancer progression and immune evasion.

Molecular Mechanisms of CMV-Induced Oncogenesis

CMV encodes several proteins implicated in oncogenic processes. Immediate early (IE) proteins of CMV can manipulate host cell transcriptional programs, driving dysregulated cell cycle progression and survival [30]. The viral chemokine receptor homolog US28 has been shown to activate signaling pathways such as NF-κB and PI3K/Akt, promoting angiogenesis and cellular migration—hallmarks of cancer progression [31].
Moreover, CMV infection can inhibit apoptosis by upregulating anti-apoptotic proteins like Bcl-2 and modulating tumor suppressors, allowing infected cells to evade programmed cell death [32]. The virus induces pro-inflammatory cytokines and growth factors, remodeling the tumor microenvironment to favor cancer growth [33].
CMV-mediated downregulation of MHC class I molecules and interference with antigen presentation impairs cytotoxic T lymphocyte recognition, providing a mechanism for immune evasion within the tumor milieu [34]. Collectively, these mechanisms suggest that CMV acts as an oncomodulatory virus, facilitating tumor progression by altering host cellular pathways and immune surveillance.

Controversies and Challenges

Despite accumulating evidence, the role of CMV in cancer remains controversial. Some investigators argue that CMV detected in tumors reflects opportunistic infection of immunosuppressed cancer patients rather than a causative agent [35]. Differences in detection methods, sample handling, and population heterogeneity have led to variability in findings across studies [36].
Technical challenges in reliably detecting CMV in tumor tissues, including sensitivity and specificity of assays, contribute to these inconsistencies [37]. Moreover, it remains difficult to definitively establish causality in the presence of high CMV seroprevalence and frequent latent infection in the general population.
Addressing these challenges requires standardized, rigorous methodologies and longitudinal studies designed to dissect temporal and causal relationships between CMV infection and cancer development.

Current Status of Antiviral and Immunotherapeutic Strategies

Therapeutic strategies targeting CMV have been primarily developed for prevention and treatment of CMV disease in immunocompromised hosts, with antiviral agents such as ganciclovir, valganciclovir, and foscarnet being the mainstay of therapy [38]. However, the potential to repurpose these antivirals in CMV-associated cancers is an area of growing interest.
Preliminary clinical studies have explored the use of ganciclovir as an adjunct in glioblastoma treatment, reporting some improvement in patient survival [39]. Immunotherapeutic approaches targeting CMV antigens expressed in tumor cells are also under investigation, including CMV-specific vaccines and adoptive transfer of CMV-specific T cells [40]. These approaches aim to harness the immune system to specifically target CMV-infected tumor cells, potentially improving treatment efficacy and outcomes.
Novel strategies including small molecule inhibitors targeting CMV proteins involved in oncogenic pathways and immune checkpoint modulation are promising avenues for future cancer therapies. Various antiviral and immunotherapeutic strategies have been explored targeting CMV in oncological settings, as summarized in Table 2.

Future Directions and Research Needs

The association between CMV and cancer demands further rigorous investigation. Future research priorities include the development and standardization of highly sensitive and specific detection techniques for CMV in tumors, large-scale epidemiological studies to establish associations, and mechanistic studies to clarify causal relationships [41].
Clinical trials are needed to evaluate the efficacy of antiviral and immunotherapeutic agents targeting CMV in cancer patients [42]. A multidisciplinary approach integrating virology, oncology, immunology, and molecular biology is essential to unravel CMV’s complex role in cancer.
Additionally, understanding the impact of CMV infection on the tumor microenvironment and immune landscape may reveal novel therapeutic targets and strategies, advancing personalized medicine in oncology.

Conclusions

Human cytomegalovirus (HCMV) has emerged as a significant focus in the study of viral oncogenesis due to its potential role as an oncomodulatory agent rather than a classical oncogenic virus. A growing body of evidence suggests that HCMV contributes to tumor progression and malignancy through diverse molecular and immunological mechanisms, including modulation of cell signaling pathways, induction of genomic instability, immune evasion, promotion of angiogenesis, and inhibition of apoptosis. These effects may enhance the tumor microenvironment and support neoplastic processes without directly initiating cellular transformation.
Despite the absence of definitive proof implicating HCMV as a primary etiological factor in cancer, its frequent detection in various tumor tissues—such as glioblastomas, colorectal cancer, and breast cancer—combined with its ability to alter host cellular behavior, underscores its relevance in cancer biology. However, the controversy surrounding causality persists, largely due to heterogeneity in detection methods, variability in viral gene expression, and the challenges in distinguishing active infection from latent or abortive replication within tumor cells.
From a clinical perspective, the concept of targeting HCMV in the context of cancer holds considerable promise. Antiviral therapies, CMV-targeted immunotherapies, and vaccine strategies are under investigation for their potential to suppress HCMV-driven tumor-promoting activities, which may translate into improved clinical outcomes. Furthermore, the presence of HCMV components in tumor tissues could serve as a prognostic or predictive biomarker, offering new avenues for patient stratification and personalized therapy.
In conclusion, while the direct oncogenic role of HCMV remains a subject of ongoing debate, its capacity to modulate the tumor microenvironment and influence cancer progression is increasingly recognized. Continued interdisciplinary research is essential to elucidate the mechanistic underpinnings of HCMV’s oncomodulatory functions and to translate these insights into innovative diagnostic tools and therapeutic interventions for CMV-associated malignancies.

Acknowledgement

  • ICMR, Ministry of Health, Govt. of India
  • KSCSTE, Govt. of Kerala

Authors Contribution

Conceptualisation & Supervision: Rajendra Pilankatta, Sameer Kumar V.B., Jordi Muntane

Writing original draft

AKM, SRA

Review & Proofreading

AKM

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Table 1. Summary of Cancer Types with CMV Detection and Clinical Relevance.
Table 1. Summary of Cancer Types with CMV Detection and Clinical Relevance.
Cancer Type Detection Methods CMV Prevalence* Evidence of Oncogenic Role Clinical Implications References
Glioblastoma PCR, IHC, in situ hybridization High CMV proteins detected in tumor tissue; promotes angiogenesis, immune evasion Potential target for antiviral/immunotherapy 6,22,23,32,41
Medulloblastoma PCR, IHC Moderate CMV antigens detected; possible role in tumor progression Therapeutic target under investigation 25
Breast Cancer PCR, IHC Low to Moderate CMV DNA and proteins found; correlation with tumor grade debated Potential prognostic marker 27
Colorectal Cancer PCR, IHC Moderate CMV presence linked to inflammation and tumor microenvironment modulation Possible therapeutic implications 26
Prostate Cancer PCR, IHC Low Limited data; CMV DNA occasionally detected Role unclear, needs further study [reference]
*Prevalence estimates vary by study and detection method.
Table 2. Antiviral and Immunotherapeutic Strategies Targeting CMV in Cancer.
Table 2. Antiviral and Immunotherapeutic Strategies Targeting CMV in Cancer.
Therapy Type Mechanism Target Cancer Type Key Findings Status References
Valganciclovir CMV DNA polymerase inhibitor Glioblastoma Improved survival reported in small trials Clinical trials ongoing 32,39,41
CMV Peptide Vaccines Stimulate CMV-specific T-cell response Glioblastoma Phase I trials show immunogenicity and safety Early clinical trials 42
Adoptive T-cell therapy Infusion of CMV-specific cytotoxic T-cells Glioblastoma Potential to enhance anti-tumor immunity Preclinical/early trials 40
Antiviral drugs (Ganciclovir, Foscarnet) Inhibit CMV replication Various Limited data on effectiveness in solid tumors Off-label/experimental 18,38
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