Molecular and microenvironmental drivers of malignant transformation from oral potentially malignant disorders to...

Oral potentially malignant disorders (OPMDs) comprise a diverse group of oral mucosal lesions with a variable but significant risk of progression to oral squamous cell carcinoma (OSCC). However, predicting malignant transformation remains a major clinical challenge due to the limited reliability of conventional histopathological grading and the inherent biological heterogeneity of these lesions. Increasing evidence indicates that OPMD progression is a dynamic, multistep process driven by the convergence of molecular alterations and microenvironmental remodeling. This review synthesizes current knowledge on the key mechanisms underlying OPMD-to-OSCC transformation, focusing on the interplay between genomic instability, epigenetic dysregulation, chronic inflammation, and tumor microenvironment evolution. Dysregulation of critical signaling pathways, including TGF-β, PI3K/AKT, MAPK, Wnt/β-catenin, and NF-κB, contributes to epithelial plasticity, immune evasion, fibrosis, and sustained oncogenic signaling. Special attention is given to oral submucous fibrosis as a high-risk model, highlighting the role of extracellular matrix stiffening and mechanotransduction pathways such as YAP/TAZ in promoting malignant progression. The limitations of morphology-based diagnostics underscore the need for molecularly informed risk assessment in modern healthcare. Emerging biomarkers including genetic, epigenetic, transcriptomic, proteomic, metabolomic, and exosomal signatures offer promising tools for early detection and stratification of high-risk lesions. Furthermore, integration of multi-omics data with artificial intelligence based predictive models holds significant potential for advancing precision oncology in oral cancer. Collectively, this review supports an evolutionary shift in understanding OPMDs as dynamic and evolving biological systems rather than static precursor lesions. Elucidating the molecular and microenvironmental convergence driving malignant transformation provides a foundation for improved early detection, risk prediction, and development of targeted preventive and therapeutic strategies in OSCC.