Background <p>Oral squamous cell carcinoma (OSCC) is a marked invasive epithelial tumor with limited treatment efficacy, especially in advanced stages. The immunosuppressive nature of the tumor microenvironment (TME) is a major contributor to OSCC development and therapeutic resistance. Peroxisome proliferator-activated receptor gamma (PPARγ) is known to influence tumor biology in a multifaceted and context-specific manner. The objective of this research was to explore the role of PPARγ in modulating the TME and its impact on OSCC progression.</p> Methods <p>A 4NQO-induced OSCC model was used to verify PPARγ overexpression by Immunohistochemistry (IHC). Bulk RNA-seq and single-cell RNA-seq analyses were employed to dissect PPARγ-driven tumor-promoting mechanisms. Co-cultivation of OSCC cells and CD4 + T cells in vitro, combined with subcutaneous tumor model in vivo, was employed to investigate the influence of PPARγ on Th17 cells differentiation.</p> Results <p>Inhibition of PPARγ significantly suppressed OSCC cell growth and downregulated IL-17 pathway–related genes, including IL-17C. PPARγ promoted Th17 cells differentiation via transcriptional upregulation of CEBPA/IL-17C/IL-17A signaling pathway. Evidence from cell-based and animal experiments confirmed that GW9662 treatment impaired Th17 cells polarization and reduced expression of CEBPA, IL-17C, and IL-17A.</p> Conclusion <p>This study identifies a novel PPARγ/CEBPA/IL-17C/IL-17A signaling axis that promotes Th17 differentiation and contributes to tumor-associated inflammation in OSCC. Targeting PPARγ represents a promising strategy to inhibit tumor progression and modulate the immune microenvironment, providing new insight into immunotherapeutic approaches for OSCC.</p>