成纤维细胞生长因子受体2（FGFR2）经常因过表达或突变而被激活，而异常的成纤维细胞生长因子（FGF）/ FGFR信号通路与结肠直肠癌（CRC）的发生、发展和不良预后有关。我们的初步分析发现，纤溶酶原激活物抑制剂-1（PAI-1）的表达可能与FGF/ FGFR信号有关，但它们在肿瘤免疫微环境中的作用仍不清楚。在本研究中，我们观察到CRC患者中PAI-1表达明显高于存活率较低的患者。在结肠癌细胞中，PAI-1受FGF/ FGFR2调节，并参与M2型巨噬细胞极化。在机制上，抑制JAK2 / STAT3信号通路可导致PAI-1下调。此外，磷酸化STAT3激活可上调PAI-1。在体内，肿瘤携带的鼠模型中，FGFR2过表达表明PAI-1抑制剂可以挽救FGFR2 / PAI-1轴诱导的M2型巨噬细胞极化，从而导致有效的免疫活性和肿瘤抑制。此外，PAI-1抑制剂和抗PD-1治疗的联合使用在小鼠中展示了更优异的抗肿瘤活性。这些发现为研究肿瘤恶化的分子机制提供了新的见解，并为CRC治疗提供了潜在的治疗靶点。版权所有©2023作者。由Elsevier B.V.出版。保留所有权利。

Fibroblast growth factor receptor 2 (FGFR2) is frequently activated by overexpression or mutation, and an abnormal fibroblast growth factor (FGF)/FGFR signaling pathway is associated with the occurrence, development, and poor prognosis of colorectal cancer (CRC). Our preliminary analysis found that plasminogen activator inhibitor-1 (PAI-1) expression may be related to FGF/FGFR signaling, however, their role in the tumor immune microenvironment remains unclear. In this study, we observed markedly higher PAI-1 expression in CRC patients with poor survival rates. PAI-1 is regulated by FGF/FGFR2 in colon cancer cells and is involved in M2 macrophage polarization. Mechanistically, inhibiting the JAK2/STAT3 signaling pathway could cause PAI-1 downregulation. Furthermore, the activation of phosphorylated STAT3 upregulated PAI-1. In vivo, FGFR2 overexpression in tumor-bearing mouse models suggested that a PAI-1 inhibitor could rescue FGFR2/PAI-1 axis-induced M2 macrophage polarization, which leads to effective immune activity and tumor suppression. Moreover, the combination of a PAI-1 inhibitor and anti-PD-1 therapy exhibited superior antitumor activity in mice. These findings offer novel insights into the molecular mechanisms underlying tumor deterioration and provide potential therapeutic targets for CRC treatment.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.