A myeloid immunosuppressive phenotype defines primary refractoriness to atezolizumab Plus bevacizumab in hepatocellular caarcinoma

Background: Despite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma (HCC), primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant challenge. Methods: We analysed 1296 patients with HCC treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by Society for the Immunotherapy of Cancer (SITC) criteria. We performed a multi-parametric analysis of pre-treatment tumour tissue, including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry (IMC) and RNA sequencing (RNAseq) to evaluate differences in the tumour microenvironment (TME) of PRef versus responding patients. Two independent cohorts were further used to refine the TME characterisation through single-cell RNA sequencing (n=20) and IMC (n=16). We employed conditional inference tree analyses to provide a hierarchical organisation of PRef determinants. Results: Among 677 AB-real and 378 trial patients evaluable by SITC criteria, PRef identified inferior median OS in comparison with responding patients (AB-real: 7.3 vs. 31.5 months,p<0.001; Trials: 10.8 vs. NR, p<0.001). PRef patients exhibited higher baseline systemic inflammation (NLR≥3), a distinctively immunosuppressive TME enriched in CD163+ tumour-associated macrophages, vascular cancer-associated fibroblasts, a higher Treg/Teff ratio, and pro-tumour supportive cellular interactions. RNAseq 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 HCC, 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 HCC - and identify a distinct immunomolecular 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.