Qi Yuchen, Mou Jie, Huang Jiadong, Li Tianyi, Leng Chunru, Si Yameng
The Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou 221000, China; School of Stomatology, Xuzhou Medical University, Xuzhou 221000, China.
Xuzhou Medical University School of Pharmacy, Xuzhou 221000, China.
Int Immunopharmacol. 2025 Oct 30;164:115406. doi: 10.1016/j.intimp.2025.115406. Epub 2025 Aug 27.
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.
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.
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).
This study has developed new targets for the treatment of OSCC and provided new ideas for clinical exploration of immunotherapy resistance.
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.
尽管已确定PAK5与癌症进展之间存在临床联系，但其在口腔鳞状细胞癌（OSCC）中的生物学作用仍不清楚。本研究旨在阐明PAK5与OSCC之间的关系。免疫抑制性肿瘤微环境（TME）是导致免疫治疗内在抗性的关键因素。识别调节这种TME的分子对于克服这种抗性至关重要。在此，我们通过PAK5抑制剂联合帕博利珠单抗治疗研究PAK5在免疫治疗抗性中的作用，评估PAK5作为治疗靶点，并推进联合疗法以解决OSCC免疫治疗中的耐药性问题。
利用生物信息学分析和临床采样来表征PAK5与OSCC之间的关系。分别使用CCK-8、集落形成、伤口愈合和Transwell实验评估PAK5对OSCC细胞增殖、迁移和侵袭的影响。在体内，建立异种移植肿瘤模型，通过监测治疗后肿瘤体积和重量来评估治疗效果。通过苏木精-伊红（H&E）染色评估药物安全性。采用蛋白质免疫印迹法、免疫荧光法和酶联免疫吸附测定法来阐明潜在机制。
PAK5在OSCC中过表达，并促进OSCC细胞的增殖、迁移和侵袭。动物研究表明，PAK5小分子抑制剂与帕博利珠单抗联合治疗具有卓越的治疗效果，肿瘤体积和重量显著减小。从机制上讲，这种联合治疗有效减轻了免疫抑制并重塑了肿瘤微环境（TME）。
本研究为OSCC的治疗开发了新的靶点，并为免疫治疗抗性的临床探索提供了新思路。
PAK5可能作为一种新型治疗靶点，是临床开发中联合治疗的有前景的候选者，以应对免疫治疗中的耐药性挑战。
