The Axis Modulates the Immunosuppressive Tumor Microenvironment and Predicts Immunotherapy Response in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy that is notorious for its dismal prognosis. Dysregulation of the tumor microenvironment (TME) in HCC has emerged as a key hallmark in determining disease progression and the response to immunotherapy. The aim of this study was to identify novel TME regulators that contribute to therapeutic resistance, thus providing mechanistic insights for targeted interventions. The expression of was evaluated in the the Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC) and Guangxi HCC cohorts, and its clinicopathological significance was assessed. RNA sequencing and bioinformatics analyses were performed to elucidate the potential impact of elevated levels. Immunohistochemistry (IHC) and single-cell mass cytometry (CyTOF) were employed to examine the cellular composition of the tumor microenvironment. The biological effects of on cell proliferation and migration were studied in vitro using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide(MTT) and wound healing assays, while its impact on tumor growth was evaluated in vivo in a nude mouse model. Transcriptomic and single-cell proteomic analyses were integrated to explore the mechanism by which affects the progression of HCC. The expression of was significantly up-regulated in both HCC tissues and cell lines ( < 0.05). RNA sequencing analyses revealed a significant positive correlation between expression and immunosuppression, and between expression and extracellular matrix(ECM)-related molecular features. Single-cell mass cytometry revealed two immunosuppressive cell clusters that were enriched in HCC patients with high expression. Moreover, was associated with immune exclusion and ECM remodeling signals in the TME of HCC. overexpression was associated with the expression of the tumor inflammatory marker (), and a inhibitor could partially reverse the biological phenotype associated with expression in HCC cells ( < 0.05). Further transcriptome analysis in immunotherapy cohorts suggested the axis might have predictive value for the response to immunotherapy. Our results suggest that may serve as a biomarker for the prognosis of HCC patients and may also be a predictive biomarker for the response to immunotherapy, enabling more precise and personalized HCC treatment.