Clinical readiness of biomarker-integrated triage after positive hrHPV screening: viral mRNA, host methylation, and immune-context markers — a structured narrative review

High-risk human papillomavirus (hrHPV)-based screening has improved cervical cancer prevention, but an hrHPV-positive result does not necessarily indicate clinically meaningful precancer. Most infections are transient, whereas only a minority persist, acquire transforming activity, and progress to cervical intraepithelial neoplasia grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+). Effective triage is therefore required to identify women who need immediate colposcopy or intensified surveillance while minimizing unnecessary referral, psychological burden, and overtreatment. This structured narrative review evaluates biomarker-integrated triage after positive hrHPV screening across three biologically distinct dimensions: viral oncogenic activity, host-cell transformation, and immune context. HPV E6/E7 messenger RNA reflects active viral oncogene transcription and may provide greater specificity than HPV DNA testing in selected assay- and population-specific settings. However, mRNA assays are not interchangeable, and negative results cannot independently exclude CIN2 + or CIN3+. Self-collected mRNA workflows may show reduced clinical sensitivity in some device–assay combinations and therefore require separate assay-, device-, and workflow-specific validation. Host DNA methylation biomarkers, including PAX1/JAM3 and other methylation panels, capture transformation-associated epigenetic alterations and may be useful for refining risk in women with non-16/18 hrHPV infection, persistent HPV positivity with negative cytology, or borderline cytological abnormalities. Nevertheless, their clinical applicability remains dependent on assay standardization, cut-off validation, external validation, and direct comparison with established triage tools. Immune-context markers, including interleukin-17-related indicators, provide mechanistic insight into inflammatory activation, impaired viral clearance, and cervical immune remodeling, but current evidence is predominantly exploratory. Their assay reproducibility, workflow feasibility, cost-effectiveness, and real-world clinical utility remain insufficiently established for routine triage. A potentially valuable near-term research direction is the prospective evaluation of stepwise virus–host triage models against guideline-relevant comparators, including HPV16/18 or extended genotyping, cytology, and p16/Ki-67 dual-stain testing. Clinical translation will require platform-specific validation, standardized thresholds, longitudinal assessment of missed CIN3 + and surveillance safety, decision-curve and cost-effectiveness analyses, and evidence of real-world net clinical benefit. Biomarkers should therefore be judged not by biological association alone, but by whether they improve risk-based management after positive hrHPV screening.