Masuda Takeshi, Hattori Noboru
Department of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University.
Biomed J. 2025 Sep 5:100911. doi: 10.1016/j.bj.2025.100911.
Lung cancer is the leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs), chemotherapy, and molecular targeted therapies have improved survival rates, therapeutic resistance remains a major barrier to curative outcomes. Recently, plasminogen activator inhibitor-1 (PAI-1) has been implicated in lung cancer progression and treatment resistance.
This review summarizes the recent evidence from preclinical and clinical studies on the Role of PAI-1 in the progression and treatment resistance in lung cancer, focusing on its contribution to tumor aggressiveness and resistance to therapy. As limited evidence is available regarding its role in small cell lung cancer, this review focuses on the findings reported to date for non-small cell lung cancer (NSCLC).
PAI-1 promoted tumor invasion, angiogenesis, and epithelial-mesenchymal transition (EMT), thereby facilitating cancer progression. Elevated PAI-1 expression in tumor tissues and plasma is correlated with advanced disease stages and poor prognosis. Genetic polymorphisms such as A15T, which affect PAI-1 stability, are also associated with unfavorable outcomes. PAI-1 contributes to radiotherapy resistance through the hypoxia-induced upregulation of AKT/ERK signaling, chemotherapy by activating cancer-associated fibroblasts, and targeted therapies via integrin-mediated EMT. Moreover, it enhances immune evasion by promoting programmed cell death-ligand 1 expression and creating an immunosuppressive tumor microenvironment.
PAI-1 is a key regulator of tumor progression and therapeutic resistance in NSCLC. Targeting PAI-1 may offer a novel strategy to overcome resistance to multiple treatment modalities, and future research should focus on developing PAI-1-based biomarkers and therapeutic combinations for both NSCLC.
肺癌是全球癌症相关死亡的主要原因。尽管免疫检查点抑制剂（ICI）、化疗和分子靶向治疗提高了生存率，但治疗耐药性仍然是实现治愈性结果的主要障碍。最近，纤溶酶原激活物抑制剂-1（PAI-1）被认为与肺癌进展和治疗耐药性有关。
本综述总结了临床前和临床研究中关于PAI-1在肺癌进展和治疗耐药性中作用的最新证据，重点关注其对肿瘤侵袭性和治疗耐药性的影响。由于关于其在小细胞肺癌中作用的证据有限，本综述重点关注迄今为止非小细胞肺癌（NSCLC）的研究结果。
PAI-1促进肿瘤侵袭、血管生成和上皮-间质转化（EMT），从而促进癌症进展。肿瘤组织和血浆中PAI-1表达升高与疾病晚期和预后不良相关。影响PAI-1稳定性的A15T等基因多态性也与不良预后相关。PAI-1通过缺氧诱导的AKT/ERK信号上调导致放疗耐药，通过激活癌症相关成纤维细胞导致化疗耐药，并通过整合素介导的EMT导致靶向治疗耐药。此外，它通过促进程序性细胞死亡配体1表达和创造免疫抑制性肿瘤微环境来增强免疫逃逸。
PAI-1是NSCLC肿瘤进展和治疗耐药的关键调节因子。靶向PAI-1可能提供一种克服对多种治疗方式耐药的新策略，未来的研究应专注于开发基于PAI-1的生物标志物以及NSCLC的治疗组合。
