Neurogranin facilitates maintaining the immunosuppressive state of hepatocellular carcinoma by promoting TGF-β1 secretion

Immunotherapy has revolutionized cancer treatment, but its effectiveness is limited due to the complexity of the tumor immune microenvironment. Identifying reliable biomarkers that can predict immunotherapy response is essential for enhancing treatment strategies. This study evaluated the potential of Neurogranin (NRGN) as a biomarker for prognosis and immunotherapy response across multiple cancers. Through pan-cancer bioinformatics analyses, coupled with in vitro and in vivo experiments, we explored NRGN's differential expression across various cancer types and its role in the immune microenvironment. Our approach involved database mining, immune genomic feature correlation analyses, and functional validation through NRGN knockdown and overexpression studies. The results revealed differential NRGN expression across cancers, particularly hepatocellular carcinoma (HCC), where elevated levels correlated with immune evasion, poor prognosis, and upregulation of checkpoint genes like TGFB1. NRGN modulated T cell activity and macrophage polarization by regulating the TGF-β pathway through interaction with TCF4 and promoting its nuclear localization, driving tumor progression. Targeting TGF-β with anti-TGF-β and anti-PD-1 antibodies additively inhibited HCC in an Nrgn-dependent manner in mice. These findings indicate that NRGN may serve as a promising immunotherapeutic target, as its overexpression predicts poor prognosis and immune evasion, thereby offering insights for improving immunotherapy and developing new treatments.