Cancer-Associated Fibroblast-Derived GDF15 Induces Oxidative Stress and Neutrophil Infiltration in Head and Neck Squamous Cell Carcinoma through the PI3K/AKT/STAT3 Axis Cascade

Background: Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor of the oral mucosal epithelium. The high incidence of recurrence and metastasis presents substantial challenges for treatment, underscoring the complex molecular landscape underlying the disease. The purpose of this work is to clarify how HNSCC tumor cells and cancer-associated fibroblasts (CAFs) interact. Methods: Spatial transcriptome sequencing and single-cell RNA sequencing had been employed to describe the biological characteristics of CAFs in HNSCC. The biological connection between CAFs and tumor cells was verified by molecular interaction experiments. In addition, the regulatory effect of CAFs on oxidative stress in tumor cells and the phenotypic conversion of neutrophils were explored through a coculture system, a knockdown/overexpression method, flow cytometry, and animal experiments. Finally, potential small-molecule inhibitors were screened by molecular dynamics simulation and validated through in vitro and in vivo assays. Results: Growth differentiation factor 15 (GDF15) promoted tumor cell growth and invasion by enhancing PCNA clamp associated factor (PCLAF) transcription through interferon regulatory factor 5 modulation. Its interaction with the receptor GDNF family receptor alpha like (GFRAL) triggered chronic inflammatory signaling via the phosphatidylinositol-3 kinase/protein kinase b/signal transducer and activator of transcription 3 pathway, which led to oxidative stress imbalance and contributed to tumor progression and the development of drug resistance. Moreover, GDF15 activated the extracellular signal-regulated kinase 1/2 pathway through tumor necrosis factor-α, thereby facilitating neutrophil infiltration and promoting lung metastasis in HNSCC. Notably, risperidone (SM-2) emerged as a potential inhibitory regulator capable of disrupting the cascade effects mediated by the GDF15–GFRAL axis, underscoring its therapeutic relevance. Conclusion: This study identifies the GDF15–GFRAL signaling axis as a critical regulator of oxidative stress and immune evasion in HNSCC and demonstrates that the novel small-molecule SM-2 effectively targets this pathway, highlighting its potential as a promising therapeutic strategy.