Decoding the trans-kingdom signaling pathways between human host cells and virome components in cancer progression

Abstract

Background: Viral elements, such as human papillomavirus (HPV), Epstein–Barr virus (EBV), endogenous retroviruses (e.g., human endogenous retrovirus K), and bacteriophages, are known to regulate oncogenic signaling. To assess the ability of patient-level virome activity and host-pathway disruption to predict patient survival, we developed a Trans-Kingdom Signaling Index (TKSI). Methods: We examined 320 patients with HPV-positive head and neck squamous cell carcinoma, HPV-positive cervical cancer, and EBV-positive stomach adenocarcinoma. Viral features, including HPV E6/E7, virome modules, phage CpG DNA, phage structural proteins, and viral double-stranded RNA, along with tumor RNA sequencing data, were analyzed using single-sample Gene Set Enrichment Analysis on six host pathways: nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), cGAS–STING, p53, MYC, EMT, and PD-L1. A coupling matrix (K) was constructed to connect viral modules to host pathways, and TKSI was calculated, normalized, and dichotomized into TKSI-high and TKSI-low. Results: TKSI values followed an approximately normal distribution and stratified survival independent of tumor type. Patients with high TKSI exhibited lower overall survival (median overall survival 18.2 vs. 29.4 months) and an adjusted hazard ratio of 1.6 (log-rank p=0.018). TKSI–survival associations were robust, with bootstrapped 95% confidence intervals supporting these findings. Observed virome–host interactions corresponded to known mechanisms, including HPV-mediated suppression of p53, EBV microRNA-mediated PD-L1 expression, human endogenous retrovirus K-mediated activation of MYC, and phage CpG–TLR9–NF-κB. Conclusion: Virome–host interactions significantly influence cancer prognosis and signaling. TKSI integrates viral and host mechanisms to improve risk stratification. Relevance for patients: TKSI-derived virome–human quantification enhances patient stratification and may guide the development of virome-responsive biomarkers for precision oncology.

Keywords

Cyclic GMP–AMP synthase–stimulator of interferon genes / Epstein–Barr virus microRNA / Human papillomavirus E6 and E7 oncoproteins / Immune checkpoint / Systems oncology / Trans-Kingdom Signaling Index / Toll-like receptor 9 / Virome

Acknowledgements

The authors sincerely thank the participating institutions and collaborators for their support throughout this study. Special appreciation goes to Skyline University Nigeria for providing academic and technical guidance.

Funding

None.

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

Conceptualization: Miracle Uwa Livinus, Mustapha Abdulsalam Data curation: Musa Ojeba Innocent, Mustapha Abdulsalam, Madinat Hassan, Shehu Sani Formal analysis: Musa Ojeba Innocent, Mustapha Abdulsalam, Madinat Hassan, Shehu Sani Investigation: Mustapha Abdulsalam, Musa Ojeba Innocent, Stephen Olaide Aremu, Katimu Yusuf Methodology: Miracle Uwa Livinus, Sunday Zeal Bala, Katimu Yusuf, Madinat Hassan Writing – original draft: Miracle Uwa Livinus, Mustapha Abdulsalam, Sunday Zeal Bala, Stephen Olaide Aremu Writing – review & editing: All authors

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki. Ethical approval for the use of de-identified patient-derived datasets was originally obtained by contributing institutions, including The Cancer Genome Atlas and associated repositories. All data analyzed in this study were publicly available and fully anonymized; therefore, no additional patient consent was required.

Consent for publication

Not applicable.

Availability of data

Not applicable.

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