Integrated proteomics and metabolomics analysis revealed that macrophage-related signals may be potential biomarkers for oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with poor prognosis, yet the protein-level and metabolic alterations driving disease progression remain poorly characterized. Here, we integrated multi-omics analysis combining proteomics, metabolomics, spatial transcriptomics, and single-cell RNA sequencing data to systematically compare OSCC tumors with matched adjacent non-tumor tissues. Our proteomic profiling identified significant upregulation of immune-related proteins ARPC4 in OSCC, which correlated with poor patient survival. Notably, C1QC-positive macrophages (Macro_C1QC) were identified as the primary source of these dysregulated proteins, with high Macro_C1QC infiltration serving as an independent prognostic marker. Integrated proteo-metabolomic analysis revealed profound dysregulation of tryptophan metabolism pathways, suggesting a potential association with macrophage-mediated immunosuppression in the OSCC microenvironment. These findings collectively indicate that tryptophan metabolic imbalance might promote OSCC progression by reprogramming the phenotype of macrophages. In summary, our study not only delineates the proteomic and metabolomic landscape of OSCC but also identifies immune-related proteins ARPC4 along with Macro_C1QC macrophages as novel prognostic biomarkers.