ArticleJournal of hepatology2025
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma.
Article in Journal of hepatology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A dual-level Bayesian network meta-analysis of first-line immunotherapy in advanced hepatocellular carcinoma: strategy-level and regimen-level evidence.Frontiers in immunology · 2026Pooled it
- Integrated single-cell multi-omics characterization reveals lipid-associated macrophage-mediated immunosuppression in neoadjuvant immunotherapy of hepatocellular carcinoma.Nature communications · 2026Trial
- Clinical Trial: Early Nivolumab Addition to Regorafenib in Patients With Hepatocellular Carcinoma in Second-Line (The GOING Trial).Alimentary pharmacology & therapeutics · 2026Trial
- Systemic treatment paradigms for unresectable and advanced hepatocellular carcinoma in Europe.The Lancet regional health. Europe · 2026Review
- Deep Learning-Assisted Prioritization of Candidate Drug Targets in Tumors Using Spatial Multi-Omics.Biology · 2026Review
- Integration of histopathology and molecular features for the classification of benign and malignant hepatocellular neoplasms.Virchows Archiv : an international journal of pathology · 2026Review
- Immunotherapy Rechallenge in HCC: A Second Chance for Response?Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- Spatiotemporal dynamics of the tumor microenvironment in hepatocellular carcinoma during combination immunotherapy.Hepatology communications · 2026Article
- CSNK2B Expression Aligns with a GDF15-Associated Immune Molecular State in Hepatocellular Carcinoma.Biomedicines · 2026Article
- Review
- Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside.Cancer cell international · 2026Review
- Optimal treatment selection for hepatocellular carcinoma in the era of immunotherapy.Journal of gastroenterology · 2026Review
- Trial design and end points in hepatocellular carcinoma: an EASL-AASLD-ILCA consensus statement.Nature reviews. Clinical oncology · 2026Article
- Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma.Nature communications · 2026Article
- Vessels encapsulating tumor clusters predict better outcomes in advanced hepatocellular carcinoma treated with atezolizumab-bevacizumab.JHEP reports : innovation in hepatology · 2026Article
- Review
- Single-Cell Transcriptomic Profiling Reveals Immunometabolic Reprogramming and Cell-Cell Communication in the Tumor Microenvironment of Human Hepatocellular Carcinoma.International journal of molecular sciences · 2026Article
- Dissecting the Transcriptomic Profile of CD163Liver cancer · 2026Article
- From Theory to Practice: Which Biomarkers Are Ready for Predicting Response in Advanced HCC?Liver international : official journal of the International Association for the Study of the Liver · 2026Review
- Vessels That Encapsulate Tumor Cluster+ Unresectable Hepatocellular Carcinomas Benefit of Antiangiogenic Therapy.Liver cancer · 2026Article
Corrections and comments
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Authors and funding
41 authors.
Funding
Abstract
BACKGROUND &
aimsThe combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit vs. resistance to atezo+bev.
methodsWe harnessed the power of single-cell RNA sequencing in advanced HCC to derive gene expression signatures recapitulating 21 cell phenotypes. These signatures were applied to 422 RNA-sequencing samples of patients with advanced HCC treated with atezo+bev (n = 317) vs. atezolizumab (n = 47) or sorafenib (n = 58) as comparators.
resultsWe unveiled two distinct patterns of response to atezo+bev. First, an immune-mediated response characterised by the combined presence of CD8+ T effector cells and pro-inflammatory CXCL10+ macrophages, representing an immune-rich microenvironment. Second, a non-immune, angiogenesis-related response distinguishable by a reduced expression of the VEGF co-receptor neuropilin-1 (NRP1), a biomarker that specifically predicts improved OS upon atezo+bev vs. sorafenib (p = 0.039). Primary resistance was associated with an enrichment of immunosuppressive myeloid populations, namely CD14+ monocytes and TREM2+ macrophages, and Notch pathway activation. Based on these mechanistic insights we define "Immune-competent" and "Angiogenesis-driven" molecular subgroups, each associated with a significantly longer OS with atezo+bev vs. sorafenib (p of interaction = 0.027), and a "Resistant" subset.
conclusionOur study unveils two distinct molecular subsets of clinical benefit to atezolizumab plus bevacizumab in advanced HCC ("Immune-competent" and "Angiogenesis-driven") as well as the main traits of primary resistance to this therapy, thus providing a molecular framework to stratify patients based on clinical outcome and guiding potential strategies to overcome resistance. IMPACT AND IMPLICATIONS: Atezolizumab + bevacizumab (atezo+bev) is standard of care in advanced hepatocellular carcinoma (HCC), yet molecular determinants of clinical benefit to the combination remain unclear. This study harnesses the power of single-cell RNA sequencing, deriving gene expression signatures representing 21 cell subtypes in the advanced HCC microenvironment. By applying these signatures to RNA-sequencing samples, we reveal two distinct response patterns to atezo+bev and define molecular subgroups of patients ("Immune-competent" and "Angiogenesis-driven" vs. "Resistant") with differential clinical outcomes upon treatment with atezo+bev, pointing towards the role of immunosuppressive myeloid cell types and Notch pathway activation in primary resistance to atezo+bev. These results may help refine treatment strategies and improve outcomes for patients with advanced HCC, while also guiding future research aimed at overcoming resistance mechanisms.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.