MYO1F in neutrophils is required for the response to immune checkpoint blockade therapy

作者：Yingying Qu, Wenhua Liang, Mingzhu Yu, Chenhui Wang, Min Luo, Lin Zhong, Zhigang Li, Feng Wang · 发表于：The Journal of Experimental Medicine · 年份：2025 · DOI：10.1084/jem.20241957 · 被引用次数：4 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Tumor-associated neutrophils (TANs) represent a significant barrier to the effectiveness of immune checkpoint blockade (ICB) therapy. A comprehensive understanding of TANs' regulatory mechanisms is therefore essential for predicting ICB efficacy and improving immunotherapy strategies. Our study reveals that MYO1F is selectively downregulated in neutrophils within both human cancers and murine tumor models, showing a negative correlation with ICB response. Mechanistically, MYO1F normally inhibits neutrophil immunosuppression and proliferation by restraining STAT3 activity. However, during tumorigenesis, tumor-derived TGF-β1 disrupts the binding of SPI1 to intron 8 of Myo1f via DNA methylation, thereby suppressing Myo1f transcription. The resultant decrease in MYO1F reprograms neutrophils into an immunosuppressive state through the STAT3-dependent signaling pathways. This immunosuppressive state further contributes to tumor microenvironment (TME) remodeling by inducing CTL exhaustion. These findings establish MYO1F as a critical regulator within TANs, highlighting its significant role in modulating ICB therapy efficacy.