AccScience Publishing / JCTR / Online First / DOI: 10.36922/JCTR025420074
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ORIGINAL ARTICLE

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

Miracle Uwa Livinus1* ,  Mustapha Abdulsalam2 ,  Innocent Ojeba Musa2 ,  Stephen Olaide Aremu3 ,  Sunday Zeal Bala4 ,  Madinat Hassan5,6,7 ,  Shehu Sani8 ,  Katimu Yusuf9
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1 Department of Biochemistry, Skyline University Nigeria, Kano State, Nigeria
2 Department of Microbiology, Skyline University Nigeria, Kano State, Nigeria
3 Department of Medicine and Surgery, Faculty of General Medicine, Siberian State Medical University, Tomsk, Tomsk Oblast, Russian Federation
4 Department of Pharmaceutical Sciences, University of Maryland Eastern Shore, Princess Anne, Maryland, United States of America
5 Foresight Institute of Research and Translation, Kigali, Rwanda
6 Khayr Cancer Health Initiative, Kaduna, Kaduna State, Nigeria
7 Department of Biological Sciences, Faculty of Sciences, Air Force Institute of Technology (AFIT), Kaduna, Kaduna State, Nigeria
8 Department of Community Health, School of Public Health, University of Port Harcourt, Port Harcourt, Rivers State, Nigeria
9 Department of Microbiology, Federal University Gashua, Gashua, Yobe State, Nigeria
JCTR, 025420074 https://doi.org/10.36922/JCTR025420074
Received: 16 October 2025 | Revised: 22 January 2026 | Accepted: 22 January 2026 | Published online: 19 February 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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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
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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Journal of Clinical and Translational Research, Electronic ISSN: 2424-810X Print ISSN: 2382-6533, Published by AccScience Publishing
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