Systemic immune activation coexists with compartment-specific regulatory enrichment in matched blood, peritumor, and tumor tissue from advanced oral squamous cell carcinoma.

Background: Oral squamous cell carcinoma (OSCC) is the most prevalent form of oral cancer and is characterized by a poor prognosis and frequent immune evasion. While the tumor microenvironment (TME) plays a central role in modulating responses to therapy, its relationship with systemic immune signatures remains poorly understood. Methods: We performed high-dimensional immune profiling in matched peripheral blood, adjacent non-neoplastic peritumor mucosa, and tumor tissue from Human Papillomavirus (HPV)-negative, treatment-naïve patients with advanced OSCC. Soluble mediators were quantified by multiplex immunoassay, and immune cell phenotypes were assessed by multiparametric flow cytometry. Compartment-specific patterns were evaluated using paired and unpaired comparisons, dimensionality reduction, ordinal trend analysis, unsupervised clustering, and correlation networks. Results: Seventeen plasma mediators were significantly elevated in OSCC patients compared with healthy donors. Paired cellular profiling identified compartment-specific differences across blood, peritumor and tumor, and selected PD-1 Conclusions: Advanced OSCC is associated with distinct systemic and tissue immune profiles. These exploratory findings identify compartment-specific immune features and selected monotonic trends that warrant future spatial, functional, and clinical validation.