Biology-aligned cervical cancer screening: target-centric biomarkers and next-generation diagnostic platforms

Cervical cancer remains a leading cause of cancer-related mortality among women worldwide, with mortality disproportionately concentrated in low-and middle-income countries (LMICs), where screening infrastructure is limited. Although persistent high-risk human papillomavirus (hrHPV) infection drives nearly all cervical cancers through a prolonged preinvasive window, making the disease both preventable and detectable, current screening modalities face biological and operational limitations that constrain their global impact. Cytology-based methods suffer from moderate sensitivity and subjective interpretations. HPV DNA testing is highly sensitive, it lacks specificity for transforming infections and shifts the diagnostic burden toward triage and colposcopy. Meanwhile, visual inspection methods are accessible, they offer limited reproducibility. In this review, we adopt a target-centric diagnostic framework that organizes cervical cancer screening not by detection platform but by the biological class of the marker being interrogated. We first examined the molecular pathogenesis of cervical carcinogenesis, including HPV genotype-specific biology, viral integration dynamics, oncogene-driven transformation, and epigenetic consolidation, to establish the biological rationale for each biomarker category. We then systematically evaluated conventional screening modalities and their limitations before reviewing emerging diagnostic technologies across four target domains: HPV-derived markers (DNA, mRNA, capsid proteins), host cell-cycle regulators (p16^INK4a, Ki-67), non-protein biomarkers (biothiols, volatile metabolites), and marker-free platforms (Raman/FT-IR spectroscopy, AI-assisted cytopathology). Particular emphasis is placed on point-of-care (POC) deployability, noninvasive sampling strategies, and the integration of multilayered risk stratification into scalable screening pathways. By mapping diagnostic innovation onto the biological continuum of cervical carcinogenesis, this review provides a conceptual foundation for developing next-generation screening approaches that align molecular precision with global accessibility, thereby supporting progress toward the World Health Organization goal of cervical cancer elimination.