Radio-immunomics for non-invasive immune phenotyping and therapeutic stratification in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by substantial biological and immune heterogeneity that contributes to variable responses to immune checkpoint inhibitors (ICIs) and limits reliable treatment selection. Radio-immunomics has emerged as an interdisciplinary framework that integrates quantitative imaging with pathological, molecular, and immune profiling to develop candidate non-invasive imaging correlates of the tumor immune microenvironment (TIME). This review critically examines the immunobiological landscape of HCC, clinical evidence for ICI-based systemic therapy, the role of radiotherapy and radioembolization, and the biological and clinical rationale for combining radiotherapy with immune checkpoint blockade. Particular emphasis is placed on the conceptual distinction between radiogenomics and radio-immunomics and on the requirement for biological validation of imaging-derived immune biomarkers. Emerging HCC studies demonstrate that CT- and MRI-based radiomic signatures can be associated with CD8⁺ T-cell infiltration, immune-related transcriptomic programs, hypoxic–immune phenotypes, macrophage–fibroblast spatial barriers, and tertiary lymphoid structures. Longitudinal radiomics may also provide information on treatment response and evolving resistance, although direct correspondence between temporal imaging changes and specific immune mechanisms remains insufficiently established. Current evidence is predominantly retrospective or derived from relatively small prospective cohorts, and radio-immunomic biomarkers are not yet validated for routine treatment selection. Clinical translation will require harmonized imaging and analytical pipelines, spatially matched pathological and molecular validation, independent multicenter evaluation, prospective studies with predefined endpoints, and demonstration of incremental clinical utility. Radio-immunomics may ultimately complement tissue-based profiling by enabling non-invasive assessment of spatial and temporal heterogeneity, but its role in precision HCC management remains investigational.