FTO activates PD-L1 promotes immunosuppression in breast cancer via the m6A/YTHDF3/PDK1 axis under hypoxic conditions

作者：Siyu Wang, Xingda Zhang, Quanrun Chen, Hao Wu, Shihan Cao, Shilu Zhao, Guozheng Li, Jianyu Wang, Yajie Gong, Xinheng Wang, Da Pang, Song Gao · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.12.026 · 被引用次数：36 · 研究领域：RNA modifications and cancer、Cancer, Hypoxia, and Metabolism、Ubiquitin and proteasome pathways

INTRODUCTION: Altered epigenetic reprogramming enables breast cancer cells to adapt to hypoxic stress. Hypoxic microenvironment can alter immune cell infiltration and function, limiting the effectiveness of immunotherapy. OBJECTIVES: The study aimed to identify how fat mass and obesity-associated protein (FTO) helps breast cancer cells cope with the hypoxic microenvironment and the mechanisms behind breast cancer cell resistance to tumor immunity. METHODS: Clinical samples were utilized to analyze the impact of FTO on breast cancer progression and the effect of programmed cell death protein 1/ programmed cell death 1 ligand 1(PD-1/PD-L1) immune checkpoint inhibitor treatment. Utilized MeRIP-seq and mRNA-seq to analyze the downstream genes regulated by FTO under hypoxia. Methylation modification regulation of PDK1 by FTO was clarified using RIP. Then mouse models were utilized to analyze the efficacy of inhibiting FTO and 3-Phosphoinositide-dependent protein kinase 1(PDK1) in combination with PD-1/PD-L1 immune checkpoint inhibitor treatment. RESULT: A modification sites on PDK1 mRNA, preventing YTH domain family 3(YTHDF3) from recognizing and binding to these sites, thereby inhibiting the degradation of PDK1 mRNA. Overexpression of PDK1 activates the AKT/STAT3 pathway, leading to enhanced PD-L1 expression. Targeting the FTO and PDK1-AKT pathways with FB23 and BX-912 inhibit breast cancer growth, enhance cytotoxic T lymphocyte (CTL) activity, and enhance the effectiveness of th...