Immunotherapy in HCC: aetiology matters

The therapeutic landscape of advanced hepatocellular carcinoma (HCC) has undergone a paradigm shift with the advent of immune checkpoint blockade (ICB). Since the landmark success of atezolizumab plus bevacizumab in the IMbrave150 trial, immunotherapy has become the standard of care for advanced HCC. Despite these advances, a central unresolved question continues to shape the field: does HCC aetiology influence responsiveness or prognosis following immunotherapy?

Among all aetiological subtypes, metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC has generated substantial controversy. Early subgroup analyses suggested that patients with non-viral HCC, particularly MASLD-related HCC, might derive less benefit from ICB than those with viral HCC, leading to the widely cited concept that MASLD-related HCC represents an ‘immune-resistant’ subtype.^{1 2} However, subsequent studies reported comparable or even superior outcomes in patients with MASLD-related HCC or steatotic tumours treated with ICB-based regimens.^{3 4} Rather than reflecting purely technical or cohort-specific differences, these inconsistent observations may point to a more fundamental issue: MASLD-related HCC is likely not a biologically uniform disease and should not be viewed as a uniformly ‘hot’ or ‘cold’ tumour. Previous studies frequently grouped MASLD-related HCC into a single category despite substantial heterogeneity in inflammatory status, fibrotic background and concomitant viral infection.⁵ In hepatitis B virus (HBV)-endemic regions, a considerable proportion of patients classified as having MASLD-related HCC may concurrently harbour chronic HBV infection, potentially reshaping the immune microenvironment and therapeutic responsiveness. Such heterogeneity may partly explain why previous studies have reported inconsistent therapeutic outcomes across MASLD-related HCC cohorts.

In a recent paper published in the Journal of Hepatology, Zhang and colleagues provided an important and timely contribution to this debate.⁶ This study redefined the population of patients with MASLD-related HCC who derive benefit from immunotherapy, and advanced precision immunotherapy in HCC by shifting from an idealised single-aetiology classification to a more clinically relevant, multi-aetiology stratification approach reflecting real-world heterogeneity. HCC was categorised into four aetiological subgroups: HBV⁻MASLD⁻, HBV⁻MASLD⁺, HBV⁺MASLD⁻ and HBV⁺MASLD⁺ HCC. This design is particularly relevant in East Asia, where chronic HBV infection remains endemic while MASLD prevalence continues to rise rapidly alongside increasing metabolic burden.⁷ As a result, dual-aetiology HCC characterised by concurrent HBV infection and MASLD is becoming increasingly common in clinical practice. Strikingly, patients with HBV⁺MASLD⁺ HCC exhibited the most favourable prognosis following immunotherapy among all aetiological groups. Mechanistically, dual-aetiology tumours demonstrated increased CD8⁺ T-cell infiltration, stronger tumour-reactive and tumour-specific T-cell signatures and enrichment of precursor-exhausted CD8⁺ T cells, a population associated with durable ICB responses across multiple cancer types. Importantly, these findings challenge the conventional binary framework that classifies HCC as either viral or metabolic. Rather than representing a simple overlap of two coexisting risk factors, dual-aetiology HCC may constitute a distinct immunological state shaped simultaneously by chronic viral inflammation and metabolic remodelling. This observation suggests that aetiology should be considered not merely a clinical descriptor, but rather a biologically actionable dimension of tumour classification with potential implications for therapeutic responsiveness and patient stratification.

Current biomarkers for ICB response in HCC remain inadequate. Despite the important advances achieved with atezolizumab plus bevacizumab, many patients still fail to achieve durable benefit, underscoring the multifactorial nature of HCC immune heterogeneity. Beyond aetiology alone, immunotherapy responsiveness is likely shaped by complex interactions among metabolic remodelling, vascular alterations, inflammation and T-cell functional states. These observations further support the need for more integrated biomarker frameworks to refine patient stratification in HCC. In this regard, fatty acid-binding protein 4 (FABP4) may emerge as a clinically relevant marker for refining immunotherapy stratification in MASLD-related HCC.⁶ Specifically, patients with high FABP4 expression showed significantly better prognosis following immunotherapy compared with those with low FABP4 expression. This association may reflect that high FABP4 expression is linked to a more immunologically favourable tumour microenvironment, potentially including higher levels of vascular normalisation and enhanced CD8⁺ T-cell infiltration.

As dual-aetiology HCC becomes increasingly encountered, a deeper understanding of aetiology-driven immune heterogeneity will be critical for refining precision immunotherapy strategies in HCC. Whether dual-aetiology HCC represents a reproducible immunological subtype across different ethnic and geographical populations requires validation in larger prospective cohorts. Furthermore, it remains unclear whether similar aetiology-dependent immune remodelling patterns also exist in HCV-related or alcohol-related HCC. Addressing this question in broader and more diverse patient populations may help determine whether aetiology-informed immunotherapy stratification represents a more generalisable framework across distinct HCC aetiologies. In addition, the temporal relationship between HBV-associated inflammation and metabolic dysfunction during immune remodelling remains poorly understood. Future clinical trials may benefit from incorporating aetiology-informed stratification, particularly dual-aetiology status, into patient enrolment, biomarker analyses and therapeutic response assessment. Actionable design elements include: enrolment criteria should systematically document HBV markers (hepatitis B surface antigen (HBsAg), HBV DNA) and MASLD diagnostic criteria (imaging-proven or biopsy-proven steatosis without other causes), allowing classification into different aetiological subgroups; randomisation should be stratified by aetiological category to ensure balance between treatment arms; sample size calculations should account for the expected proportion of dual-aetiology HCC to preserve statistical power for subgroup analyses; FABP4 expression levels (high vs low) should be measured at baseline as a prespecified secondary stratification marker; endpoints should include aetiology-specific outcomes, such as differences of overall survival between aetiological subgroups. A deeper mechanistic understanding of aetiology-associated immune heterogeneity may help guide more effective immunotherapy strategies in HCC. For example, in FABP4-low tumours, approaches aimed at increasing endothelial FABP4 expression, promoting vascular normalisation or enhancing CD8⁺ T cell infiltration may help improve sensitivity to ICB.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.