Radiogenomics predicts immune microenvironment heterogeneity and response to combination immunotherapy in hepatocellular carcinoma.
[BACKGROUND] The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents is the preferred first-line therapy option for patients with advanced hepatocellular carcinoma (HCC), ye
APA
Xu ZG, Liu YW, et al. (2026). Radiogenomics predicts immune microenvironment heterogeneity and response to combination immunotherapy in hepatocellular carcinoma.. Journal of translational medicine, 24(1), 181. https://doi.org/10.1186/s12967-025-07627-4
MLA
Xu ZG, et al.. "Radiogenomics predicts immune microenvironment heterogeneity and response to combination immunotherapy in hepatocellular carcinoma.." Journal of translational medicine, vol. 24, no. 1, 2026, pp. 181.
PMID
41555384
Abstract
[BACKGROUND] The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents is the preferred first-line therapy option for patients with advanced hepatocellular carcinoma (HCC), yet only a subset of patients responds, urging the quest for prediction biomarkers. We aimed to integrate genomics with radiology to propose an immune-derived radiogenomics biomarker of response to such combination immunotherapy and evaluate its added value in clinical context.
[METHODS] We integrated bulk RNA sequencing (RNA-seq) and proteomics data of 994 HCC patients with single-cell RNA-seq data of 11 samples across multiple datasets to identify an immune-related signature (IRS) that may influence sensitivity or resistance to such combined immunotherapy strategy, followed by verification of selected marker genes using immunohistochemistry and cytological experiments. We then trained/validated a cross-modality radiogenomics biomarker using machine learning based on TCIA database that was further tested in multi-scale independent cohorts covering 754 HCC patients.
[RESULTS] Integrative multi-omics analysis identifed a parsimonious 2-gene prognostic signature including KPNA2 and SMG5 that was significantly associated with immune heterogeneity and response to combination immunotherapy. Machine-learning pipeline exported the optimal 4-feature radiogenomics biomarker using support vector machine that significantly discriminated prognosis (hazard ratio 1.415–1.890; < 0.05 for all) and modestly predicted response to ICI plus anti-angiogenic therapy (area under the curve 0.720–0.829) in independent retrospective series across major imaging modalities (computed tomography/magnetic resonance imaging). In a prospective neoadjuvant cohort, this biomarker also showed favorable performance for predicting pathological response and tumor recurrence, accompanied by biological validation through single-cell RNA-seq analysis of pre-treatment biopsies.
[CONCLUSIONS] Our study provides a cross-device-cross-modal radiogenomics biomarker that can improve patient selection for emerging ICI plus anti-angiogenic therapy with novel potential therapeutic targets in HCC.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-025-07627-4.
[METHODS] We integrated bulk RNA sequencing (RNA-seq) and proteomics data of 994 HCC patients with single-cell RNA-seq data of 11 samples across multiple datasets to identify an immune-related signature (IRS) that may influence sensitivity or resistance to such combined immunotherapy strategy, followed by verification of selected marker genes using immunohistochemistry and cytological experiments. We then trained/validated a cross-modality radiogenomics biomarker using machine learning based on TCIA database that was further tested in multi-scale independent cohorts covering 754 HCC patients.
[RESULTS] Integrative multi-omics analysis identifed a parsimonious 2-gene prognostic signature including KPNA2 and SMG5 that was significantly associated with immune heterogeneity and response to combination immunotherapy. Machine-learning pipeline exported the optimal 4-feature radiogenomics biomarker using support vector machine that significantly discriminated prognosis (hazard ratio 1.415–1.890; < 0.05 for all) and modestly predicted response to ICI plus anti-angiogenic therapy (area under the curve 0.720–0.829) in independent retrospective series across major imaging modalities (computed tomography/magnetic resonance imaging). In a prospective neoadjuvant cohort, this biomarker also showed favorable performance for predicting pathological response and tumor recurrence, accompanied by biological validation through single-cell RNA-seq analysis of pre-treatment biopsies.
[CONCLUSIONS] Our study provides a cross-device-cross-modal radiogenomics biomarker that can improve patient selection for emerging ICI plus anti-angiogenic therapy with novel potential therapeutic targets in HCC.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-025-07627-4.