Viral persistence and host-state remodeling in virus-associated cancers

Virus-associated cancers are not defined mechanistically by viral detection alone. To address this problem, this review organizes evidence around four related but non-equivalent analytical axes rather than around individual viruses. The first two address retained-product dependence and the regulatory architecture of retained viral material. The other two address host-state memory after viral suppression or clearance and tissue-level immune or stromal selection. Across tumor-virus systems, these questions encompass continued viral-product expression, latency, episomal or proviral genome maintenance, integration, covalently closed circular DNA (cccDNA), and host control of viral replication or transcription. Evidence must therefore be matched to the question being asked. Detection establishes presence or expression, whereas selective perturbation tests functional dependence. Genome and chromatin mapping define regulatory context, while longitudinal studies assess durable host change. Single-cell and spatial analyses identify tissue associations, but functional testing is needed before these associations are interpreted as selection or causality. The four axes may overlap within the same viral system, yet their evidentiary meanings are not interchangeable. This organization can guide experimental design for studies of viral persistence and host-state remodeling. It can also help distinguish candidate therapeutic dependencies from biomarkers of disease burden, residual risk, or immune response.