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Lookup NU author(s): Erik Ramon Gil, rabial raja, George MercesORCiD, Professor Helen ReevesORCiD, Professor Derek MannORCiD, Dr Jack LeslieORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s).Background & Aims Despite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma, primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant challenge. Methods We analysed 1,296 patients with hepatocellular carcinoma treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by SITC (Society for the Immunotherapy of Cancer) criteria. We performed a multi-parametric analysis of pre-treatment tumour tissue, including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry and RNA sequencing (RNA-seq) to evaluate differences in the tumour microenvironment (TME) of patients with PRef vs. responders. Two independent cohorts were further used to refine the TME characterisation through single-cell RNA-seq (n = 20) and imaging mass cytometry (n = 16). We employed conditional inference tree analyses to provide a hierarchical organisation of PRef determinants. Results Among 677 AB-real patients and 378 trial participants evaluable by SITC criteria, PRef was associated with inferior median overall survival compared to response (AB-real: 7.3 vs. 31.5 months, p <0.001; Trials: 10.8 vs. not reached, p <0.001). Patients with PRef exhibited higher baseline systemic inflammation (neutrophil-to-lymphocyte ratio [NLR] ≥3), a distinctly immunosuppressive TME enriched in CD163+ tumour-associated macrophages and vascular cancer-associated fibroblasts, a higher Treg/Teff cell ratio, and pro-tumour supportive cellular interactions. RNA-seq of tumour tissue confirmed lower intrinsic immunogenicity in PRef samples with elevated myeloid infiltration. Conditional inference tree analysis identified IFN-γ signature downregulation combined with NLR ≥3 as the strongest contributor of PRef. Conclusions PRef to A+B identifies a distinct biological entity characterised by unopposed systemic inflammation, myeloid infiltration, and T-cell depletion. Targeting myeloid-mediated immunosuppression, particularly in patients with low IFN-γ signature expression and elevated NLR might enhance responsiveness to A+B. Impact and implications Atezolizumab plus bevacizumab represents the standard first-line treatment for unresectable hepatocellular carcinoma, yet the biological basis of early treatment failure remains poorly understood. In this multi-cohort translational study, we show that approximately 40% of patients exhibit primary refractoriness according to SITC criteria – clinically validated here for the first time in hepatocellular carcinoma – and identify a distinct immuno-molecular profile of primary refractory tumours characterised by IFN-γ pathway repression, unfavourable myeloid polarisation, and a distinct spatial immune architecture. These findings provide a biological framework that may inform the design of biomarker-stratified trials and rational combination strategies to overcome primary resistance to first-line immunotherapy.
Author(s): Lombardi P, Ramon-Gil E, Raja RQ, Brunetti L, Manfredi GF, Zhou Z, Merces G, Cappuyns S, Maria Fulgenzi CA, D'Alessio A, Torkpour A, Celsa C, Stefanini B, Yang H, Crowley F, Marron TU, Saeed A, Pinter M, Scheiner B, Huang Y-H, Lee P-C, Nishida N, Po-Ting Lin R, Dalbeni A, Vivaldi C, Masi G, Rohlen N, von Felden J, Kaseb A, Galle PR, Kudo M, Hsu W-F, Rimassa L, Parisi A, Kelley RK, Toyoda H, Pirisi M, Jabar F, Rakaee M, Cabibbo G, Camma C, Piscaglia F, Hwang S, Shin DJ, Li M, Dekervel J, Guerra N, Meyer T, Reeves HL, Bengsch B, Daniele G, Mann DA, Chon HJ, Leslie J, Pinato DJ
Publication type: Article
Publication status: Published
Journal: Journal of Hepatology
Year: 2026
Pages: Epub ahead of print
Online publication date: 15/06/2026
Acceptance date: 21/05/2026
Date deposited: 10/08/2026
ISSN (print): 0168-8278
ISSN (electronic): 1600-0641
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.jhep.2026.05.018
DOI: 10.1016/j.jhep.2026.05.018
Data Access Statement: All clinical, raw RNA-seq data for the GO30140 and IMbrave150 trials are deposited in the European Genome-Phenome Archive under accession no. EGAS00001005503. Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli. org/). Further details on Roche’s criteria for eligible studies are available at https://vivli.org/members/ourmembers. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://www.roche.com/research_and_ development/who_we_are_how_we_work/clinical_trials/our_commitment_to_ data_sharing.htm.
PubMed id: 42297215
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