MYCN/MNX1 Axis Drives NSCLC Progression by Inducing Macrophage M2 Polarization and CD8+ T Cell Apoptosis via the Wnt/β-Catenin Pathway

Abstract

Enhanced macrophage M2 polarization and CD8⁺ T cell dysfunction contribute to the pathophysiology of non-small cell lung cancer (NSCLC). Motor neuron and pancreatic homeobox 1 (MNX1) has emerged as a potential tumor-promoting player. Here, we clarified the activity of MNX1 in NSCLC. PMA-induced THP-1 M0-like macrophages or CD8⁺ T cells were co-cultured with NSCLC cells. Cell colony formation, migration, proliferation, apoptosis, and invasiveness were assessed by colony formation, wound healing, CCK-8, flow cytometry, and transwell assays, respectively. The ratio of CD206⁺ macrophages was analyzed by flow cytometry. Ki-67 expression was tested by immunofluorescence. ChIP and luciferase assays were used to evaluate the relationship between MYCN and MNX1. MNX1 was highly expressed in NSCLC, and its loss-of-function suppressed cell growth, motility, and invasiveness in NSCLC cells. MNX1 depletion also diminished macrophage M2 polarization and CD8⁺ T cell apoptosis. Mechanistically, MYCN increased MNX1 expression at the transcriptional level. MNX1 increase reversed the impact of MYCN depletion on NSCLC cell malignant behaviors, macrophage M2 polarization, and CD8⁺ T cell viability. MYCN depletion diminished the in vivo growth of A549 subcutaneous xenografts. Additionally, MNX1 increase counteracted the impact of MYCN depletion on the Wnt/β-catenin pathway. Our findings elucidate the oncogenic role of the MYCN/MNX1/Wnt/β-catenin pathway in NSCLC by driving macrophage M2 polarization and diminishing CD8⁺ T cell viability. Our study thus uncovers a novel mechanism underlying NSCLC development and highlights potential targets for combating NSCLC.