Dual-targeted lipid nanoparticles for TET3 siRNA delivery: nanobiotechnology strategy to remodel tumor immune microenvironment in hepatocellular carcinoma

BACKGROUND: 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. RESULTS: T cell exhaustion in HCC models. CONCLUSIONS: 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.