Introduction: Oral squamous cell carcinoma (OSCC) remains a leading global malignancy with low survival expectancy due to its evasion from the immune response. Immune checkpoint molecules such as programmed death ligand-1 (PDL-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) contribute to tumor immune evasion. Curcumin (Cr), combined with the bioenhancer piperine (Pip), exhibits antiproliferative and anti-inflammatory activities, yet its influence on immune checkpoint expression within a carcinogeninduced tumor microenvironment remains poorly characterized. Aim: This study evaluated the short-term effects of an intraperitoneal Cr-Pip combination on tumor progression, systemic cytokine balance, histopathological architecture, and PDL-1/CTLA-4 expression in a DMBA-induced hamster OSCC model. Methodology: Twenty male Syrian hamsters were divided into a negative control group (A), a DMBAinduced OSCC positive control group (B), and a DMBA-induced OSCC group receiving one week of intraperitoneal Cr (80 mg/kg) and Pip (1 mg/kg) (C). Tumor size, serum IL-10 and TNF-α, histopathological features, and immunohistochemical PDL-1/CTLA-4 expression were assessed and statistically compared. Conclusion: Cr-Pip treatment significantly reduced tumor burden and produced a more cohesive, less invasive histological pattern, accompanied by decreased IL-10, elevated TNF-α, and a significant increase in PDL-1 and CTLA-4 expression. These findings indicate that Cr-Pip modulates both tumor invasive behavior and the immune checkpoints, reflecting a shift toward local immune activation as well as evidence of partial tumor regression.