Experimental Models and Nanotechnology-Based Platforms in Oral Squamous Cell Carcinoma: From Tumor Biology to Translational Applications

Oral cancer, predominantly represented by oral squamous cell carcinoma (OSCC), remains a major global health burden due to its aggressive clinical behavior, high recurrence rates, and limited improvement in survival over recent decades. Despite advances in treatment modalities, patient outcomes remain poor largely due to late diagnosis, therapeutic resistance, and profound tumor heterogeneity. In particular, metabolic reprogramming has emerged as a central hallmark of oral carcinogenesis, enabling tumor cells to adapt to hypoxic and nutrient-deprived microenvironments while promoting proliferation, invasion, and treatment resistance. Traditional experimental models, including two-dimensional cell cultures and in vivo animal models, have provided important mechanistic insights. However, they fail to fully recapitulate the metabolic, structural, and cellular complexity of human tumors. Consequently, there is growing interest in more physiologically relevant platforms, such as three-dimensional spheroids, organoids, and patient-derived models, which better preserve tumor architecture and microenvironmental interactions. In parallel, multi-omics approaches are increasingly being integrated to dissect the molecular and metabolic complexity of oral cancer at unprecedented resolutions, while nanotechnology-based systems are emerging as promising tools for targeted drug delivery and improved therapeutic precision. This review discusses experimental models in oral cancer research, focusing on their ability to capture metabolic alterations and tumor heterogeneity. We further highlight their translational potential together with multi-omics integration and nanotechnology-based strategies for improving biomarker discovery, therapeutic stratification, and the development of more effective treatment approaches.