@article{Liu2025, 
author = {Wenting Liu and Ting Mei and Yantao Jiang and Jingya Wang and Mengjie Li and Liuchun Wang and Zhaoting Meng and Tingting Qin and Dingzhi Huang},
title = {Chidamide suppresses macrophage-mediated immune evasion and tumor progression in small cell lung cancer by targeting the STAT4/CCL2 signaling pathway},
year = {2025},
journal = {Cancer Biology & Medicine},
volume = {22},
number = {12},
pages = {1578-1604},
keywords = {SCLC, chidamide, CCL2, macrophage, tumor immune microenvironment, STAT4},
url = {https://www.sciopen.com/article/10.20892/j.issn.2095-3941.2024.0241},
doi = {10.20892/j.issn.2095-3941.2024.0241},
abstract = {ObjectiveThis study aimed at exploring the effects of the epigenetic regulator, chidamide, on reprogramming the immunosuppressive tumor microenvironment in small cell lung cancer (SCLC), particularly the roles in macrophage polarization and angiogenesis. The therapeutic efficacy of combining chidamide with the anti-angiogenic agent, anlotinib, for refractory SCLC was also evaluated.MethodsRNA sequencing and functional validation were performed to assess chidamide’s effects on macrophages. Signal transducer and activator of transcription 4 (STAT4)-mediated transcriptional activation of CCL2 was confirmed with ChIP-qPCR. The synergistic efficacy of chidamide in combination with anlotinib was tested in preclinical models.ResultsChidamide enhanced macrophage infiltration and induced macrophage polarization toward the anti-tumor M1 phenotype. Mechanistically, chidamide upregulated CCL2 via STAT4 transcriptional activation, thereby reshaping the tumor immune microenvironment (TIME). Combining chidamide with anlotinib synergistically suppressed tumor growth and remodeled the immunosuppressive TME in SCLC in vivo.ConclusionsChidamide reshaped the SCLC TIME by activating STAT4/CCL2, thus driving M1 macrophage polarization and enhancing anti-tumor immunity. Our findings highlight coordinated TIME-targeted therapy as a translatable strategy to overcome therapeutic resistance in SCLC and provide a rationale for clinical trials examining epigenetic and anti-angiogenic therapeutics combinations.}
}