Single-Cell and Spatial Insights into Oral Squamous Cell Carcinoma: Towards Cell-State-Targeted Immunotherapy

Oral squamous cell carcinoma (OSCC) remains associated with substantial morbidity and mortality, and only a subset of patients derive durable benefit from immune-checkpoint blockade. Single-cell and spatial approaches reveal cellular states and tissue organization that bulk profiling cannot resolve. These findings suggest that therapeutic responses may depend on both cellular function and the local interactions that sustain it. This narrative review integrates single-cell transcriptomic, spatial, functional and clinical studies of the OSCC microenvironment. We distinguish OSCC-specific findings from broader head and neck squamous cell carcinoma and pan-cancer evidence. Computational inference, tissue association, experimental perturbation and clinical validation are considered separately. Malignant, myeloid, fibroblast, vascular and lymphoid states form spatially organized niches whose composition varies across anatomical sites and treatment settings. We examine their relevance to immune escape and chemotherapy resistance and assess strategies directed at specific cell states and intercellular circuits. Although selected circuits have functional support in experimental models, many spatial signatures remain observational and lack clinical validation. Clinical translation will require reproducible tissue assays, causal testing of candidate interactions and independent biomarker validation. Practical considerations include marker-panel selection, spatial scoring, tissue availability and the feasibility of sampling primary tumors and metastatic sites before, during and after treatment. Prospective studies must also determine whether biomarker-guided treatment improves outcomes, rather than assuming that a spatial association predicts therapeutic benefit. This review aims to critically synthesize current evidence, identify key knowledge gaps and define requirements for translating cell-state and spatial-niche insights into selective immunotherapeutic strategies for OSCC.