胰腺癌是一种致命的疾病，很大程度上对免疫疗法具有抵抗力，部分原因是肿瘤微环境（TME）中免疫抑制细胞的积累。大量证据表明，肿瘤来源的外泌体有助于胰腺癌 TME 中骨髓源性抑制细胞 (MDSC) 介导的免疫抑制活性。然而，潜在的机制仍然难以捉摸。在此，我们报告肿瘤源性外泌体中的巨噬细胞迁移抑制因子（MIF）在诱导胰腺癌中 MDSC 形成中发挥关键作用。我们在人类和小鼠胰腺癌衍生的外泌体中发现了 MIF。通过特异性 shRNA 介导的 MIF 敲低，胰腺癌来源的外泌体促进 MDSC 分化的能力被消除。这种表型是通过重新表达 MIF 野生型而不是互变异构酶无效突变体或硫醇蛋白氧化还原酶无效突变体来挽救的，这表明两个 MIF 酶活性位点在胰腺癌中外泌体诱导的 MDSC 形成中发挥作用。 RNA 测序数据表明，MIF 互变异构酶调节 MDSC 分化、募集和激活所需基因的表达。因此，我们开发了一种 MIF 互变异构酶抑制剂 IPG1576。该抑制剂在体外有效抑制外泌体诱导的 MDSC 分化，并减少原位胰腺癌模型中的肿瘤生长，这与 TME 中 MDSC 数量减少和 CD8 T 细胞浸润增加有关。总的来说，我们的研究结果强调了 MIF 在外泌体诱导的胰腺癌 MDSC 分化中的关键作用，并强调了 MIF 互变异构酶抑制剂逆转免疫抑制性胰腺癌微环境的潜力，从而增强抗癌免疫反应。

Pancreatic cancer is a deadly disease that is largely resistant to immunotherapy, in part because of the accumulation of immunosuppressive cells in the tumor microenvironment (TME). Much evidence suggests that tumor-derived exosomes contribute to the immunosuppressive activity mediated by myeloid-derived suppressor cells (MDSCs) within the pancreatic cancer TME. However, the underlying mechanisms remain elusive. Herein, we report that macrophage migration inhibitory factor (MIF) in tumor-derived exosomes has a key role in inducing MDSC formation in pancreatic cancer. We identified MIF in both human and murine pancreatic cancer-derived exosomes. Upon specific shRNA-mediated knockdown of MIF, the ability of pancreatic cancer-derived exosomes to promote MDSC differentiation was abrogated. This phenotype was rescued by re-expression of the wildtype form of MIF rather than a tautomerase-null mutant or a thiol-protein oxidoreductase-null mutant, indicating that both MIF enzyme activity sites play a role in exosome-induced MDSC formation in pancreatic cancer. RNA sequencing data indicated that MIF tautomerase regulated the expression of genes required for MDSC differentiation, recruitment, and activation. We therefore developed a MIF tautomerase inhibitor, IPG1576. The inhibitor effectively inhibited exosome-induced MDSC differentiation in vitro and reduced tumor growth in an orthotopic pancreatic cancer model, which was associated with decreased numbers of MDSCs and increased infiltration of CD8+ T cells in the TME. Collectively, our findings highlight a pivotal role for MIF in exosome-induced MDSC differentiation in pancreatic cancer and underscore the potential of MIF tautomerase inhibitors to reverse the immunosuppressive pancreatic cancer microenvironment, thereby augmenting anticancer immune responses.