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Background Oral squamous cell carcinoma (OSCC) is an aggressive cancer with a high mortality rate. Recent advances in highly multiplexed imaging analysis of the tumor immune microenvironment (TIME) provide unprecedented opportunities for biomarker discovery and immunomodulatory therapy. We hypothesized that imaging mass cytometry (IMC), a high-dimensional imaging technique that combines principles of mass cytometry with laser scanning spatial resolution on tissue samples, would reveal distinct TIME characteristics and spatial intercellular interaction associated with histopathological grades of OSCC.Methods We conducted a retrospective cohort study using formalin-fixed, paraffin-embedded (FFPE) tongue biopsies from 24 OSCC patients. These samples, obtained from the University of the Pacific, Arthur A. Dugoni School of Dentistry, included 13 well-differentiated, 10 moderately differentiated, and one poorly differentiated histological diagnoses. We applied a 40-plex IMC and comprehensively characterized the signaling activity, abundance, and spatial distribution of immune cells adjacent to the tumor invasive front.Results Our integrative machine-learning pipeline, which combined robust feature selection with multivariate predictive modeling, accurately classified tumors by their histological grade (Area Under the Curve [AUC]: 0.88, p=3.6e-08). Correlation analysis on intercellular interactions showed phenotypical and functional features in tumor front were more similar to those in stromal area while distinct from those in tumor core. The similarity between tumor front and stroma were more in well-differentiated grade than the other two grades.Conclusions This study establishes a robust modeling framework for distilling complex IMC data to classify OSCC histological grades and uncovering intercellular association in TIME to facilitate prognostic biomarker discovery.Acknowledgements We acknowledge the funding support from University of the Pacific Research Enrichment Award and NIGMS (R16GM150790).Ethics Approval The study was approved by the University of the Pacific Institutional Review Board (IRB2021-161).