Inducible T-Cell Co-Stimulator Emerges During Chronic Liver Disease Progression and Defines a T-Cell–Inflamed Immune State in Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) arises within chronic liver disease and is molded by complex immune remodeling. Inducible T-cell costimulator (ICOS) is an immune checkpoint associated with T-cell activation, but its timing and role across disease progression remain unclear. This study aimed to clarify the stage-specific regulation of ICOS and determine its role in molding immune architecture during hepatocellular carcinoma development. Methods We conducted staged transcriptomic profiling integrating early metabolic liver dysfunction (GSE89632), advanced inflammatory remodeling and HCC (GSE164760), and external validation in The Cancer Genome Atlas Liver Hepatocellular Carcinoma cohort (TCGA-LIHC). ICOS dynamics were evaluated across disease stages, followed by pathway enrichment, immune signature profiling, multivariable modeling, and unsupervised immune ecosystem stratification. Results ICOS expression was stable in early disease but increased significantly during advanced inflammatory remodeling and malignant transformation. ICOS-high tumors exhibited coordinated enrichment of interferon, costimulatory, inhibitory, and effector T-cell programs, showing a stable T-cell–inflamed immune architecture. In TCGA-LIHC, ICOS expression was independent of viral etiology and tumor stage but remained tightly associated with immune exhaustion signatures after multivariable adjustment. Unsupervised clustering defined an ICOS-enriched immune subtype, distinct from tumor burden and not independently predictive of survival. Conclusions ICOS emerges during advanced liver disease and remains as a structural regulator of immune architecture in HCC. These outcomes position ICOS as a marker of immune ecosystem state rather than tumor progression per se. Looking ahead, ICOS-defined immune states could serve as a practical basis for stratifying patients in future interventional studies, enabling personalized selection for ICOS agonist or antagonist therapies.