PPARγ accelerates OSCC progression via Th17 polarization and CEBPA/IL-17C signaling.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.