The inhibitory effect of M2 macrophage-derived exosomes on gefitinib resistant lung adenocarcinoma cells through the MIF/TIMP1/CD74 axis.

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.