We greatly appreciate the insightful correspondence to our editorial from the authors [1]. We fully agree with the authors that this study warrants further validation of the immune signature score (ISS) and its simplified version (ISS10) in larger cohorts, representing more non-Asian patients and metabolic (liver) diseases to confirm their clinical utility [2,3]. We also agree that adoption of emerging technologies such as liquid biopsy will enhance their clinical applicability and enable exploration of logistically most sensible assay modalities [4]. In addition, the single-cell and spatial omic profiling assays will provide insight into the cellular sources of ISS/ISS10 in the hepatocellular carcinoma (HCC) tumor immune microenvironment [5]. Furthermore, integration with the rapidly evolving digital pathology methods may enhance their applicability in broader clinical contexts and environment with limited access to such omics assays [6].

It is encouraging to observe association of ISS/ISS10 with responses to various immune checkpoint inhibitor -based regimens that involve anti-PD-1, anti-PD-L1, anti-CTLA-4, and anti-VEGF currently approved for the treatment of advanced HCC [7]. Further assessment for the new classes of immunologic agents such as anti-TIGIT will be needed in future studies [8]. Their response-predictive capability should be evaluated for each individual agent and combinatory regimen, and therefore, acquisition of biospecimens, particularly tissue samples, will be critical, perhaps along with other candidate biomarkers for their costeffective assessment. In summary, we anticipate further evaluation of ISS/ISS10 toward their clinical translation to improve the management and treatment outcomes of patients with HCC.