Epigenetic modulation with nanosatellite triggers tumoricidal immunity for hepatocellular carcinoma treatment

Ying Qu, Chen Chen, Feifei Sun, Shijia Liu, Guozhi Zhao, Zhongxi Zhao, Chang Liu, Xinyi Jiang () and Tao Li ()
Additional contact information
Ying Qu: Shandong University
Chen Chen: Shandong University
Feifei Sun: Cheeloo College of Medicine, Shandong University
Shijia Liu: Shandong University
Guozhi Zhao: Shandong University
Zhongxi Zhao: Shandong University
Chang Liu: Shandong University
Xinyi Jiang: Shandong University
Tao Li: Shandong University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Epi-immunotherapy appears promising for hepatocellular carcinoma (HCC) treatment, but immunosuppressive macrophages limit the capacity of epigenetic regulation to activate T cell-mediated tumoricidal immunity. Here we report an epi-immune nanosatellite (stEiNS) that co-delivers siRNA targeting the YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) alongside the histone deacetylase IIa inhibitor TMP195, enabling epigenetic reprogramming of HCC tumor cells and M2 macrophages to enhance the immunotherapeutic response. stEiNS assembles size-mismatched nanoparticles via dynamic locks in a satellite-like structure, enabling deep tissue penetration. Knockdown of YTHDF1 by stEiNS in HCC cells, along with stEiNS-driven antitumor macrophage phenotype induction, intensifies macrophages-cytotoxic T lymphocytes interactions with tumor cells. stEiNS suppresses TNF/NF-κB signaling in tumor cells to inhibit CCL2-driven recruitment of myeloid-derived suppressor cells while activating the IFNγ/STAT1 pathway in M2-phenotype macrophages to promote their polarization toward an M1 phenotype. Collectively, these effects trigger robust tumoricidal immunity, leading to efficient tumor eradication, as validated in patient-derived tumor organoids, orthotopic HCC models, and recurrence models. In summary, we establish a dual-targeting stEiNS with promising epi-immunotherapeutic potential against advanced HCC and diverse malignancies.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-61974-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61974-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-61974-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().