MORF4L2 induces immunosuppressive microenvironment and immunotherapy resistance through GRHL2/MORF4L2/H4K12Ac/CSF1 axis in triple-negative breast cancer

作者：Xin-Yi Sui, Shuo-Wen Cao, Xiao-Qing Song, Xiyu Liu, Chao Chen, Qingya Yan, Zhiqiang Wang, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Ding Ma, Yi Xiao, Song‐Yang Wu, Ying Xu, Zhi-Ming Shao, Lei Fan · 发表于：Biomarker Research · 年份：2025 · DOI：10.1186/s40364-024-00719-1 · 被引用次数：5 · 研究领域：Immune cells in cancer、Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers

BACKGROUND: Although immunotherapy has achieved great progress in advanced triple-negative breast cancer (TNBC), there are still numerous patients who do not benefit from immunotherapy. Therefore, identification of the key molecule that induces immune escape and clarification of its specific mechanism in TNBC are urgently needed. METHODS: In this research, single cell sequencing and bulk sequencing were conducted for biomarker screening. Immunohistochemistry, multiplex immunofluorescence, and orthotopic TNBC tumor model were applied in identifying the key molecule driving immune escape. At the mechanical level, RNA sequencing, in vitro co-culturing system, flow cytometry, Western blotting, ELISA, and real-time qPCR were carried out. RESULTS: Mortality factor 4 like 2 (MORF4L2) expression is significantly up-regulated among patients who developed anti-PD1 resistance. MORF4L2 enhances anti-PD1 resistance by inducing the chemotaxis of macrophage infiltration and promoting their polarization towards the alternative activation phenotype (M2), thus creating an immunosuppressive microenvironment. Mechanistically, MORF4L2 actes as part of NuA4 histone acetyltransferase (HAT) complex, contributes to to histone 4 lysine 12 acetylation (H4K12Ac) and activates the downstream transcription of macrophage colony-stimulating factor (CSF1). CSF1 is secreted by tumor cells and binds to the macrophage-surface CSF1 receptor (CSF1R), which chemotactically converted and polarized macrophages to th...