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

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

  • J Nanobiotechnology. 2025 Jul 1;23(1):469. doi: 10.1186/s12951-025-03538-0.
Ziqi Guo 1 2 3,  Qiuling Huang 1,  Zhenzhen Cui 1,  Cheng Yang 4 5 6,  Liu Yang 7
Affiliations

Affiliations

  • 1 College of Life Sciences, Guangxi Normal University, No. 15 Yucai Road, Qixing District, Guilin, Guangxi, 541004, China.
  • 2 Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, 541004, Guilin, China.
  • 3 Joint Medical Research Center of Guangxi Normal University & Guilin Hospital of Chinese Traditional and Western Medicine, Guangxi Normal University, 541004, Guilin, China.
  • 4 College of Life Sciences, Guangxi Normal University, No. 15 Yucai Road, Qixing District, Guilin, Guangxi, 541004, China. yang_cheng1016@163.com.
  • 5 Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, 541004, Guilin, China. yang_cheng1016@163.com.
  • 6 Joint Medical Research Center of Guangxi Normal University & Guilin Hospital of Chinese Traditional and Western Medicine, Guangxi Normal University, 541004, Guilin, China. yang_cheng1016@163.com.
  • 7 College of Life Sciences, Guangxi Normal University, No. 15 Yucai Road, Qixing District, Guilin, Guangxi, 541004, China. yangl@gxnu.edu.cn.
PMID: 40598231 DOI: 10.1186/s12951-025-03538-0
Abstract

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 (m6A) 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:

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

Keywords

Hepatocellular carcinoma immunotherapy; Myeloid-derived suppressor cells; YTHDF2; m6A modification; pH-responsive nanoparticles; siRNA therapy.

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