Insights into immunotherapy response in hepatocellular carcinoma: from blood to tissue studies

In recent years, multiple systemic therapies based on immune checkpoint inhibitors (ICIs) have been introduced in the first-line setting for advanced hepatocellular carcinoma (HCC). However, the rate of primary resistance to ICIs stresses the need for companion biomarkers capable of predicting therapeutic efficacy upfront to guide therapy selection and adaptation. We performed a longitudinal immunophenotypic analysis of the total white blood cell population (CD45+) and their immune subsets in patients treated with atezolizumab-bevacizumab, aiming to identify early, non-invasive biomarkers of response. In parallel, we tested an organic electrochemical transistor (OECT)-based co-culture assay to evaluate the activation induced by immunotherapy of patient-derived peripheral blood mononuclear cells (PBMC) as a complementary tool to better characterize immune dynamics over treatment. High baseline CTLA-4+ lymphocytes were associated with treatment efficacy. Moreover, an early decrease in circulating CTLA-4+ CD45+ blood cells predicted response to atezolizumab-bevacizumab and correlated with longer overall survival (OS). The OECT assay effectively discriminated responders from non-responders, further enhancing the predictive potential of a dynamic biomarker. Our findings suggest that combining immunophenotypic profiling with functional immune assay may provide a robust strategy to predict response to ICIs, improving patient stratification and tailored treatment choices in advanced HCC.