Epigenetic modulation with nanosatellite triggers tumoricidal immunity for hepatocellular carcinoma treatment

作者：Ying Qu, Chen Chen, Feifei Sun, Shijia Liu, Guozhi Zhao, Zhongxi Zhao, Chang Liu, Xinyi Jiang, Tao Li · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61974-w · 被引用次数：13 · 研究领域：Immune cells in cancer、Epigenetics and DNA Methylation、Nanoplatforms for cancer theranostics

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. Epi-immunotherapy appears promising for hepatocellular carcinoma (H...