Peng Jingcui, Zhang Yan, Li Bin, He Xin, Ding Cuimin, Hu Wenxia
Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University, NO. 12 Jiankang Road, Shijiazhuang, 050000, Hebei, China.
Department of Cancer Testing Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
Sci Rep. 2025 Aug 5;15(1):28482. doi: 10.1038/s41598-025-13948-7.
Lung adenocarcinoma (LA) ranks among the most common malignant tumors worldwide. M2 macrophage-derived exosomes have been implicated in regulating LA progression and drug resistance. However, whether proteins encapsulated in these exosomes contribute to gefitinib resistance in LA remains to be elucidated. This study investigates the role of tissue inhibitor of metalloproteinase 1 (TIMP1) in mediating LA resistance to gefitinib. We demonstrated that M2 macrophages-derived exosomes enhanced the sensitivity of gefitinib-resistant LA cell lines (P < 0.05). Bioinformatics analyses validated the correlation of TIMP1 expression with LA progression and patient survival. Depletion of TIMP1 in M2 macrophage-derived exosomes suppressed the proliferation of gefitinib-resistant LA cells. Additionally, we confirmed that TIMP1 interacts with cluster of differentiation 74 (CD74), a process linked to the proliferation and migration of gefitinib-resistant LA cells. Additionally, this study validated that TIMP1 mediates the interaction between CD74 and macrophage migration inhibitory factor (MIF), potentially activating the PI3K/AKT signaling pathway. Collectively, these findings demonstrate that TIMP1 in M2 macrophage-derived exosomes facilitate the binding of MIF to CD74 in LA cells, thereby attenuating gefitinib resistance.
肺腺癌（LA）是全球最常见的恶性肿瘤之一。M2巨噬细胞衍生的外泌体与LA的进展和耐药性有关。然而，这些外泌体中包裹的蛋白质是否导致LA对吉非替尼耐药仍有待阐明。本研究调查金属蛋白酶组织抑制剂1（TIMP1）在介导LA对吉非替尼耐药中的作用。我们证明M2巨噬细胞衍生的外泌体增强了吉非替尼耐药LA细胞系的敏感性（P < 0.05）。生物信息学分析验证了TIMP1表达与LA进展和患者生存的相关性。M2巨噬细胞衍生的外泌体中TIMP1的缺失抑制了吉非替尼耐药LA细胞的增殖。此外，我们证实TIMP1与分化簇74（CD74）相互作用，这一过程与吉非替尼耐药LA细胞的增殖和迁移有关。此外，本研究验证了TIMP1介导CD74与巨噬细胞迁移抑制因子（MIF）之间的相互作用，可能激活PI3K/AKT信号通路。总的来说，这些发现表明M2巨噬细胞衍生的外泌体中的TIMP1促进了MIF与LA细胞中CD74的结合，从而减弱了吉非替尼耐药性。
