Saliva-based genomic signatures for early detection of oral squamous cell carcinoma: the state and perspectives of translation

Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer morbidity and mortality globally, and prognosis is closely related to the stage at diagnosis. Although advances in surgery, radiotherapy, and systemic therapies have improved outcomes, late presentation remains a major limitation to survivability. Saliva has emerged as a promising noninvasive diagnostic biofluid due to its proximity to tumors, ease of repeated collection, and the presence of tumor-derived nucleic acids. From 2020 to 2024, research increasingly focused on integrated genomic signatures combining somatic mutations, DNA methylation patterns, and RNA-based biomarkers (including mRNA, microRNA, and other noncoding RNAs) in whole saliva, cell-free fractions, and extracellular vesicles. Technological advancements such as digital polymerase chain reaction (PCR), targeted next-generation sequencing, and computational modeling have enhanced sensitivity for detecting low-abundance tumor signals and enabled longitudinal monitoring strategies. However, translation into routine clinical practice remains limited because of pre-analytical heterogeneity, inflammatory confounding, batch effects, late-stage enriched cohorts, and lack of large prospective multicenter validation. This review synthesizes current evidence, evaluates analytical and clinical readiness, and proposes a translational roadmap for clinical integration.