Metabolic crosstalk between oral microbiota and the host in OSCC: emerging roles of microbial metabolites in tumor initiation and progression.

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy characterized by profound metabolic reprogramming and a persistently poor clinical outcome. Beyond genetic and environmental risk factors, growing evidence indicates that dysbiosis of the oral microbiome is associated with metabolic perturbations observed in OSCC and may contribute to tumor initiation and progression. Microbiome-derived metabolites represent a previously underappreciated layer of cancer metabolism, linking microbial activity to host metabolic states, epigenetic regulation, and immune dysfunction within the tumor microenvironment. In this review, we provide a comprehensive synthesis of current evidence highlighting how microbial metabolites shape metabolic vulnerabilities in OSCC through the microbiome-metabolite-host axis. We focus on key metabolite classes, including short-chain fatty acids, tryptophan-derived metabolites, sulfur-containing compounds, and other emerging metabolic intermediates, and discuss their roles in modulating cellular energy metabolism, epigenetic remodeling, oxidative stress responses, and immune evasion. Particular emphasis is placed on the context-dependent and often dualistic functions of metabolites such as butyrate, which can exert tumor-suppressive or tumor-promoting effects depending on microbial source, concentration, and local inflammatory conditions. By integrating insights from metabolomics, microbial functional profiling, and mechanistic studies, this review underscores microbial metabolism as an integral component of OSCC pathobiology. Recognizing microbial metabolites as active metabolic regulators rather than passive byproducts provides a conceptual framework for identifying novel biomarkers and metabolic intervention strategies in OSCC.