Fujimura Taku, Muto Yusuke, Asano Yoshihide
Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
Biomolecules. 2025 Sep 13;15(9):1317. doi: 10.3390/biom15091317.
Plasminogen activator inhibitor-1 (PAI-1), a key regulator of fibrinolysis, has emerged as a critical stromal factor that contributes to tumor progression in various malignancies, including skin cancers. Beyond its classical role in inhibiting plasminogen activators, PAI-1 exerts pleiotropic effects within the tumor microenvironment, promoting immunosuppression, angiogenesis, and extracellular matrix remodeling. This review highlights the tumor-promoting functions of PAI-1 in melanoma, cutaneous squamous cell carcinoma, cutaneous angiosarcoma and cutaneous T-cell lymphoma, with a particular focus on its modulation of tumor-associated macrophages, cancer-associated fibroblasts, and endothelial cells. We also discuss recent preclinical and clinical studies targeting PAI-1, including TM5614, a novel oral PAI-1 inhibitor currently under investigation in phase II /III trials. By summarizing the multifaceted roles of PAI-1 and its impact on the immune and stromal landscape of skin malignancies, this review provides a rationale for PAI-1 as a promising therapeutic target and calls for further clinical validation of PAI-1-directed therapies.
纤溶酶原激活物抑制剂-1（PAI-1）是纤维蛋白溶解的关键调节因子，已成为一种关键的基质因子，在包括皮肤癌在内的各种恶性肿瘤中促进肿瘤进展。除了其在抑制纤溶酶原激活物方面的经典作用外，PAI-1在肿瘤微环境中发挥多效性作用，促进免疫抑制、血管生成和细胞外基质重塑。本综述重点介绍了PAI-1在黑色素瘤、皮肤鳞状细胞癌、皮肤血管肉瘤和皮肤T细胞淋巴瘤中的促肿瘤功能，特别关注其对肿瘤相关巨噬细胞、癌症相关成纤维细胞和内皮细胞的调节作用。我们还讨论了针对PAI-1的近期临床前和临床研究，包括TM5614，这是一种新型口服PAI-1抑制剂，目前正在进行II/III期试验。通过总结PAI-1的多方面作用及其对皮肤恶性肿瘤免疫和基质格局的影响，本综述为PAI-1作为一个有前景的治疗靶点提供了理论依据，并呼吁对PAI-1导向疗法进行进一步的临床验证。
