Nanoscale Immune Activator for Enhancing CD8+ T Cell Infiltration in Hepatocellular Carcinoma

Abstract

The infiltration of CD8+ T cells into the hepatocellular carcinoma (HCC) microenvironment is a well-established determinant of immunotherapy efficacy and patient prognosis. However, the regulatory mechanisms governing this process and the therapeutic strategies capable of modulating it remain largely unexplored. Here, we identify HCC-IN-247 as a candidate compound that enhances IFNβ-driven CD8+ T cell infiltration both in vitro and in vivo. Mechanistic investigations reveal that the long noncoding RNA LINC02084 directly interacts with the transcription factor GLIS1 and facilitates its recruitment to the IFNβ promoter. HCC-IN-247 was identified through screening to target the LINC02084-GLIS1 binding interface, thereby stabilizing this RNA–protein complex. Stabilization of the complex significantly enhances IFNβ transcription, which in turn upregulates CXCL10 and CXCL11 expression and promotes CD8+ T cell infiltration. Furthermore, this study engineered a nanoparticle-based delivery system, designated Lip@RA@BSA-PD-L1/IN-247, for the codelivery of HCC-IN-247 and the anti-PD-L1 antibody atezolizumab in HCC treatment. These nanoparticles exhibited robust tumor-specific accumulation and elicited potent synergistic antitumor activity against HCC in mice. Collectively, our findings establish HCC-IN-247 as an activator of the tumor immune microenvironment and provide a preclinical basis for a combined immunotherapeutic approach to HCC.