MIF as a master regulator in macrophage-induced chemotherapy resistance in esophageal squamous cell carcinoma

Backgroun ：Esophageal cancer is insidious, with recurrent metastasis and chemotherapy resistance as primary reasons for treatment failure. Recent interest has focused on the molecular mechanisms of tumor-associated macrophages (TAMs) in the tumor microenvironment, which remain largely unknown. Methods： TAMs were examined using both in vitro and in vivo assays. Seventy-seven normal paracancerous tissues and esophageal squamous cell carcinoma (ESCC) tumor samples were compared using immunohistochemical methods. Molecular mechanisms were identified using Transwell, Western blotting, Fluorescence-assisted cell sorting, CCK 8, and reverse transcriptase–polymerase chain reaction assays. Results: M2 TAMs were significantly elevated in ESCC tissues. M2 TAMs contributed to ESCC development and resistance to treatment both in vitro and in vivo . Elevated CD163 + TAMs in patients with ESCC correlate with an unfavorable prognosis. We found that TAMs release macrophage migration inhibitory factor (MIF), which regulates the expression of B-cell lymphoma 2 (Bcl-2), P-glycoprotein 1 (P-gp), and Bcl-2 associated X (Bax) to promote drug resistance and stimulate phosphoinositol 3-kinase (PI3K)–protein kinase B (AKT) signaling. Conclusion: Our findings demonstrate that MIF performs a functional role in the macrophage-mediated resistance of ESCC cells to cisplatin and that targeting MIF may serve as a strategy for molecular therapy.