Remodeling mechanisms and intervention strategies of the oral mucosal immune barrier

The oral mucosa serves as the primary line of defense against exogenous pathogens and antigens, and its barrier function is critical for both local oral health and systemic well-being. The oral mucosal barrier forms a multilevel defense system consisting of physical, chemical, microbial, and cellular barriers, and its dynamic remodeling relies on an intricate network among epithelial cells, immune cells and the microbiota. Epithelial cells act as immune sentinels to coordinate immune responses, while innate and adaptive immune cells mediate immediate defense, precise regulation and immune memory respectively. The oral microbiota also consolidates the barrier function by resisting colonization of pathogens, and through metabolic activities and other pathways. This finely balanced network can be perturbed by local factors such as infection, autoimmune oral diseases and oral cancer, as well as systemic factors including diabetes and tumor chemoradiotherapy, leading to barrier dysfunction. A dysfunctional oral mucosa can exacerbate local lesions, and induce or worsen systemic metabolic and inflammatory diseases through the oral-systemic axis. In recent years, the application of cutting-edge technologies such as single-cell sequencing and spatial transcriptomics has deepened our understanding of the molecular and cellular mechanisms underlying oral barrier remodeling, and spurred the development of targeted and diversified intervention approaches, including microbiota-targeted regulation, immune signaling pathway modulation, soluble biological scaffolds, and nanocarrier-based drug delivery. This review elaborates on the composition and remodeling processes of the oral mucosal immune barrier, the consequences of barrier dysfunction, and the novel therapeutic strategies for its restoration and regulation. It also highlights the current limitations in research, such as the lack of integrated mechanistic studies and standardized protocols, which warrants integration of basic research and clinical practice. The aim of this review is to guide the development of novel therapies for oral mucosal barrier-related diseases and provide a scientific basis for the integrated management of oral and systemic health.