Immune Patterns Shape Liver Hepatocellular Carcinoma Prognosis

Patterns of immune cell infiltration (ICI) and tumor genetic variability are key factors affecting liver hepatocellular carcinoma (LIHC) outcomes and treatment response. Yet, their precise roles remain unclear. This study investigates how these immune and genetic factors shape LIHC progression and identifies regulatory genes that could enhance immunotherapy effectiveness.

We analyzed LIHC datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), applying CIBERSORT and ESTIMATE algorithms to evaluate the tumor immune microenvironment (TIME) and calculate tumor mutational burden (TMB). ICI scoring was performed to identify survival-associated patterns, and gene set enrichment analysis, weighted gene coexpression network analysis (WGCNA), and machine learning were employed to uncover immunoregulatory genes. The role of CST7 in ICI and PD-1 blockade response was validated in mouse models.

ICI analysis revealed distinct survival-associated clusters, with patients in Cluster B showing significantly improved survival. Gene subtype A was linked to prolonged survival with enhanced M1 macrophage infiltration. CST7 was identified as a key regulator, promoting CD8⁺ T cell infiltration and demonstrating synergy with programmed cell death protein 1 (PD-1) antibody therapy. TMB was positively correlated with ICI patterns and served as an independent prognostic marker for LIHC outcomes.

CST7 contributes to enhanced ICI and boosts the efficacy of PD-1 immunotherapy, suggesting its potential as a therapeutic option for LIHC.