VISTA expressed on tumor cells is regulated by m6A and influences immune microenvironment through STAT3/CCL22 in NSCLC

作者：Hao Xu, Kaikai Shen, Bei Jiang, Qiuli Xu, Bingbing Li, Zhangmin Ke, Qinpei Cheng, Suhua Zhu, Dong Wang, Yong Song, Tangfeng Lv · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06818-3 · 被引用次数：1 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Ubiquitin and proteasome pathways

BACKGROUND: Immunotherapy is playing an increasingly vital role in the treatment of non-small cell lung cancer (NSCLC), yet the challenge of immune evasion remains prevalent. Therefore, investigating the regulatory mechanisms of the tumor immune microenvironment could yield significant benefits. METHODS: This study utilized differential expression analysis, WGCNA, and Lasso-Cox to analyze the GSE126044 dataset, identifying N6-methyladenosine (m6A)-related molecules that play significant roles in immunotherapy. The m6A modification of the molecule were validated through m6A dot blot, MeRIP, RNA pull-down and RNA stability assays. Their impact on the biological behavior of tumor cells (TCs) was evaluated by CCK-8 assays, wound healing assays, transwell assays, co-culture experiments and flow cytometry. Furthermore, RNA sequencing was conducted to uncover downstream pathways and cytokines, followed by subsequent validation. Lastly, validation was carried out in vivo. RESULTS: Through bioinformatics analysis, we identified that V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) serves a crucial role in immunotherapy and that its expression is regulated by m6A. It was subsequently confirmed that METTL3 enhances the m6A modification levels of VISTA mRNA, which is recognized by YTHDF1. This interaction improved the stability of VISTA mRNA, leading to increased expression of VISTA proteins on the surface of TCs. The elevated expression of VISTA boosted the cytotoxic resp...