用pH响应性小干扰RNA纳米颗粒靶向YTHDF2可抑制MYC的N6-甲基腺苷修饰并恢复肝细胞癌的抗肿瘤免疫。

Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma.

作者信息

Guo Ziqi, Huang Qiuling, Cui Zhenzhen, Yang Cheng, Yang Liu

机构信息

College of Life Sciences, Guangxi Normal University, No. 15 Yucai Road, Qixing District, Guilin, Guangxi, 541004, China.

Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, 541004, Guilin, China.

出版信息

J Nanobiotechnology. 2025 Jul 1;23(1):469. doi: 10.1186/s12951-025-03538-0.

DOI:10.1186/s12951-025-03538-0

PMID:40598231

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12210728/

Abstract

UNLABELLED

Hepatocellular carcinoma (HCC) is a highly heterogeneous and immunosuppressive malignancy that frequently exhibits poor responses to immunotherapy, primarily due to immune evasion mediated by myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Despite increasing interest in MDSC-targeted strategies, effective approaches to selectively modulate MDSC function and enhance immunotherapeutic efficacy remain limited. Recent advances in nanotechnology have led to the development of nanodrug delivery systems, particularly for small interfering RNA (siRNA), offering advantages such as protection from degradation and improved delivery specificity. However, traditional liposomal carriers often suffer from low selectivity and widespread biodistribution, increasing the risk of off-target effects. In this study, we designed a pH-responsive lipid nanoparticle (Lip@si-YTHDF2) for the targeted delivery of siRNA against YTHDF2. This approach aimed to suppress MDSC function, inhibit CSC-mediated immune escape, and enhance immunotherapy in HCC. Bioinformatic analyses of GEO and TCGA-LIHC datasets revealed elevated YTHDF2 expression in HCC and its association with poor prognosis. Functional studies in a conditional YTHDF2-knockout mouse model demonstrated that YTHDF2 regulates MDSC activity and promotes tumor progression by stabilizing MYC mRNA through N6-methyladenosine (mA) modification. Our findings demonstrated that Lip@si-YTHDF2 effectively downregulated MYC expression, diminished the immunosuppressive phenotype of MDSCs, restored T cell-mediated anti-tumor immunity, and significantly inhibited tumor growth in combination with PD-1 checkpoint blockade. This study not only elucidates a novel YTHDF2/m6A/MYC axis in immune evasion but also provides a clinically relevant siRNA delivery platform with promising therapeutic implications for improving HCC immunotherapy.

GRAPHICAL ABSTRACT

[Image: see text]

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1186/s12951-025-03538-0.

摘要

未标记

肝细胞癌（HCC）是一种高度异质性和免疫抑制性的恶性肿瘤，对免疫治疗常常反应不佳，主要是由于肿瘤微环境中髓源性抑制细胞（MDSCs）介导的免疫逃逸。尽管对靶向MDSC的策略兴趣日益增加，但选择性调节MDSC功能并提高免疫治疗疗效的有效方法仍然有限。纳米技术的最新进展导致了纳米药物递送系统的发展，特别是用于小干扰RNA（siRNA），具有防止降解和提高递送特异性等优点。然而，传统的脂质体载体通常选择性低且生物分布广泛，增加了脱靶效应的风险。在本研究中，我们设计了一种pH响应脂质纳米颗粒（Lip@si-YTHDF2）用于靶向递送针对YTHDF2的siRNA。该方法旨在抑制MDSC功能，抑制CSC介导的免疫逃逸，并增强HCC的免疫治疗。对GEO和TCGA-LIHC数据集的生物信息学分析显示，HCC中YTHDF2表达升高及其与不良预后相关。在条件性YTHDF2基因敲除小鼠模型中的功能研究表明，YTHDF2通过N6-甲基腺苷（m6A）修饰稳定MYC mRNA来调节MDSC活性并促进肿瘤进展。我们的研究结果表明，Lip@si-YTHDF2有效地下调了MYC表达，减少了MDSCs的免疫抑制表型，恢复了T细胞介导的抗肿瘤免疫力，并与PD-1检查点阻断联合显著抑制了肿瘤生长。本研究不仅阐明了免疫逃逸中一种新的YTHDF2/m6A/MYC轴，还提供了一个具有临床相关性的siRNA递送平台，对改善HCC免疫治疗具有有前景的治疗意义。