Salivary Biomarkers for Early Detection of Oral Cancer: Current Evidence, Diagnostic Potential and Future Perspectives

Background: Oral cancer is a major public health concern, particularly in South and Southeast Asia, where tobacco consumption, alcohol use and areca nut chewing contribute substantially to disease burden. Oral squamous cell carcinoma (OSCC) accounts for the majority of oral malignancies. Delayed diagnosis remains a major challenge, making the identification of reliable, non-invasive diagnostic approaches an important research priority. Objective: This review examines the role of salivary biomarkers in the early detection of oral cancer, with particular emphasis on protein biomarkers, inflammatory cytokines, nucleic acids, microRNAs, DNA methylation, metabolites, extracellular vesicles and oral microbiome-associated markers. Methods: A narrative review of relevant peer-reviewed literature was undertaken, incorporating original clinical investigations, systematic reviews, meta-analyses and recent clinical recommendations concerning salivary diagnostics in OSCC. Results: Several salivary biomarkers, including interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), CD44, CYFRA 21-1 and microRNA-31, have demonstrated potential for distinguishing individuals with OSCC from healthy controls. Salivary DNA methylation patterns, extracellular vesicles and metabolomic profiles have also emerged as promising research areas. Recent meta-analyses suggest that combinations of biomarkers may offer better diagnostic discrimination than individual markers. Nevertheless, variations in sample collection, analytical methods, patient characteristics and study populations limit the generalizability of reported findings. Conclusion: Salivary biomarkers represent a promising non-invasive approach to supporting the early detection of oral cancer. However, their clinical application remains limited by insufficient external validation, inconsistent analytical protocols and uncertain diagnostic performance in routine screening populations. Larger prospective multicentre studies are required before these tests can be recommended for routine clinical use.