PD-L1, PD-1, FOXP3, and miR-155 are emerging as key modulators of immune evasion and progression of oral squamous cell carcinoma (OSCC). This study investigated the clinical relevance of their gene expression and variants in HPV-negative OSCC. Bulk-tissue mRNA expression was evaluated in 70 patients, while variants in (rs36084323), (rs822336, rs4143815, copy number variation), (rs3761548, rs2232365), and (rs767649) were assessed in 134 patients. Expression data were validated using the TCGA cohort of 222 HPV-negative OSCC cases. Low expression was significantly associated with tumor stage (MMA: = 0.028, TCGA: = 0.025) and poor overall survival (MMA: = 0.0004, TCGA: = 0.019) in both cohorts. Declining expression correlated with advancing tumor stages, and low expression was significantly associated with poor survival in advanced stage III-IV tumors (MMA: = 0.001, TCGA: = 0.015), but not early-stage tumors. High miR-155 expression was associated with recurrence ( = 0.002) and poor survival in the MMA ( = 0.007), but not TCGA cohort. rs767649 was associated with alcohol consumption ( = 0.018). These findings point to and as potential prognostic biomarkers for HPV-negative OSCC. Stage-specific expression suggests a dynamic immunoregulatory role, with implications for optimizing immunotherapy timing. Further studies are warranted to resolve cellular context and stage-adapted immune interventions in HPV-negative OSCC.