The role and mechanism of PAK5 in the development and immunotherapy of oral squamous cell carcinoma.

OBJECTIVES: Despite the established clinical link between PAK5 and cancer progression, its biological role in oral squamous cell carcinoma (OSCC) remains unclear. This study aims to clarify the relationship between PAK5 and OSCC. The immunosuppressive tumor microenvironment (TME) is a key contributor to intrinsic resistance to immunotherapy. Identifying molecules that modulate this TME is crucial for overcoming such resistance. Here, we investigate PAK5's role in immunotherapy resistance by PAK5 inhibitors combined with pembrolizumab treatment, evaluating PAK5 as a therapeutic target and advancing combination therapies to tackle drug resistance in OSCC immunotherapy.

METHODS: Bioinformatics analysis and clinical sampling were utilized to characterize the relationship between PAK5 and OSCC. The effects of PAK5 on OSCC cell proliferation, migration, and invasion were assessed using the CCK-8, colony formation, wound-healing, and Transwell assays, respectively. In vivo, xenograft tumor model was established to evaluate therapeutic efficacy by monitoring post-treatment tumor volume and weight. Drug safety was assessed via H&E staining. Western blotting, immunofluorescence, and ELISA were employed to elucidate the underlying mechanisms.

RESULTS: PAK5 is overexpressed in OSCC and contributes to the proliferation, migration, and invasion of OSCC cells. Animal studies demonstrated that the combination of a PAK5 small-molecule inhibitor and pembrolizumab treatment exhibited superior therapeutic efficacy, with significant reductions in tumor volume and weight. Mechanistically, this combinatorial treatment effectively alleviating immunosuppression and remodeling the tumor microenvironment (TME).

CONCLUSIONS: This study has developed new targets for the treatment of OSCC and provided new ideas for clinical exploration of immunotherapy resistance.

CLINICAL SIGNIFICANCE: PAK5 may serve as a novel therapeutic target and a promising candidate for combination therapy in clinical development to address the challenge of drug resistance in immunotherapy.