Single-Cell and Spatial Omics of the Oral Cancer Ecosystem: A Scoping Review and Translational Evidence Map from Malignant Transformation to Immunotherapy Response

Background/Objectives: Oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs) exhibit marked cellular and spatial heterogeneity that is incompletely captured by bulk molecular profiling. This scoping review mapped single-cell and spatial omics applications across oral carcinogenesis and assessed the translational maturity of reported biomarkers and signatures. Methods: MEDLINE via PubMed, Scopus, and Web of Science were searched in August 2026. Human studies of OPMDs and OSCC using eligible single-cell or spatial omics were selected according to a predefined PCC framework and synthesized following JBI and PRISMA-ScR guidance. Biomarkers were classified using a prespecified, review-specific exploratory T0–T4 Translational Maturity Matrix. Results: Of 1405 records identified, 735 duplicates were removed, 670 records screened, and 64 full texts assessed; 55 studies were included. Single-cell RNA sequencing was used in 49/55 studies (89.1%), while 20/55 (36.4%) incorporated spatial omics. Recurrent themes included epithelial plasticity, fibroblast and immune remodeling, spatially organized metabolic and stromal niches, nodal dissemination, and treatment-associated immune reconfiguration. One study was T0, four T1, 27 T2, and 23 T3. T3 reflected validation in an independent patient cohort or external dataset linked to a clinical endpoint, rather than validation of a clinically qualified assay. No study reached T4. Conclusions: Single-cell and spatial omics have refined the oral cancer ecosystem, but clinical translation remains limited by platform heterogeneity, overlapping datasets, and insufficient prospective validation; the maturity framework should therefore be interpreted as an exploratory evidence-mapping tool rather than a validated measure of clinical readiness. Standardized longitudinal studies and clinically deployable assays are needed to advance precision oral oncology.