Background <p>Hepatocellular carcinoma (HCC) is characterized by a highly immunosuppressive tumor microenvironment (TME), where M2-polarized tumor-associated macrophages (TAMs) and exhausted CD8⁺ T cells limit immunotherapy efficacy. However, the upstream epigenetic mechanisms driving these phenotypes remain poorly defined, and effective nanotherapeutic strategies to reverse this immunosuppression are lacking. This study aimed to identify key epigenetic regulators of TME dysfunction and develop a targeted nanoplatform to restore antitumor immunity in HCC.</p> Results <p>Single-cell RNA sequencing identified ten-eleven translocation 3 (TET3) as highly expressed in M2 TAMs in HCC tissues. Mechanistically, TET3 promotes M2 polarization by enhancing interferon regulatory factor 4 (IRF4) transcriptional activity via hydroxymethylation, which in turn induces CD8⁺ T cell exhaustion through the CXCL12/CXCR4 axis. To target this pathway, we engineered dual-targeted lipid nanoparticles (TET3 siRNA@αmp-Lipo) modified with macrophage-specific peptides, enabling efficient and specific delivery of TET3 siRNA to M2 TAMs. In vitro experiments demonstrated the nanoparticles’ excellent biocompatibility, stability, and ability to silence TET3, inhibiting M2 polarization and restoring CD8⁺ T cell function. In vivo studies confirmed that TET3 siRNA@αmp-Lipo significantly suppressed tumor growth, reduced M2 TAM infiltration, and reversed CD8⁺ T cell exhaustion in HCC models.</p> Conclusions <p>This study identifies the TET3–IRF4 axis as a central epigenetic driver of immunosuppression in HCC and establishes TET3 siRNA@αmp-Lipo as a potent and translatable nanobiotechnology platform. By integrating targeted siRNA delivery with immune microenvironment remodeling, this strategy provides a promising approach to enhance immunotherapy for HCC and potentially other cancers with immunosuppressive TMEs.</p> Graphical abstract <p></p>