Heterogeneous mechanisms, risk stratification, and translational advances in the malignant transformation of oral potentially malignant disorders to oral squamous cell carcinoma

Oral potentially malignant disorders (OPMDs) represent important precursor conditions in the development of oral squamous cell carcinoma (OSCC) and provide a critical window for early prevention, risk assessment, and precision intervention of oral cancer. Oral leukoplakia, proliferative verrucous leukoplakia, oral erythroplakia, oral lichen planus, and oral submucous fibrosis are among the most common and clinically significant OPMDs. Although these disorders may contribute to malignant transformation through shared mechanisms, including chronic inflammation, oxidative stress, genetic and epigenetic alterations, immune dysregulation, epithelial–mesenchymal crosstalk, and microbiome dysbiosis, their predominant pathological processes and malignant transformation trajectories exhibit substantial heterogeneity. Oral leukoplakia is characterized by marked clinical and molecular heterogeneity, genomic instability, and field cancerization effects; Proliferative verrucous leukoplakia is characterized by progressive multifocal disease, an exceptionally high risk of malignant transformation, and a pronounced propensity to develop multiple primary oral cancers; oral erythroplakia is frequently associated with high-grade epithelial dysplasia or early invasive carcinoma; oral lichen planus represents an immune-mediated chronic inflammatory microenvironment that may facilitate tumorigenesis; and oral submucous fibrosis represents a matrix-driven precancerous condition primarily characterized by areca nut exposure and fibrotic extracellular matrix remodeling. In recent years, advances in single-cell omics, spatial omics, salivary liquid biopsy, digital pathology, artificial intelligence, and local drug delivery systems have provided emerging technological platforms for dynamic risk stratification, early diagnosis, and precision prevention of malignant transformation in OPMDs. This review summarizes the epidemiological links between major OPMDs and OSCC, disease-specific and shared mechanisms underlying malignant transformation, candidate biomarkers, risk stratification strategies, and advances in translational therapies. Furthermore, it aims to establish an integrated management framework for oral potentially malignant lesions based on the “epithelial–immune–stromal–microbial” niche.