Keywords
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with viral hepatitis—particularly hepatitis B virus (HBV) and hepatitis C virus (HCV)—accounting for the majority of cases globally. The advent of immune checkpoint inhibitor (ICI)-based combination therapies has transformed the first-line treatment landscape for advanced HCC, yet response rates remain heterogeneous and overall survival benefits are modest in unselected populations. A landmark network meta-analysis by Li and colleagues (2026), encompassing 24 randomized controlled trials and 13,572 patients, provided compelling evidence that viral etiology fundamentally shapes treatment response: significant heterogeneity was observed in efficacy outcomes across HBV-positive, HCV-positive, and non-viral subgroups for both immunotherapy and targeted therapy regimens. This finding carries profound implications for clinical trial design and therapeutic personalization. The tumor immune microenvironment (TIME) in viral-associated HCC is characterized by distinct immune infiltrates, T-cell exhaustion profiles, cytokine milieus, and molecular signatures that diverge substantially from non-viral HCC, providing a biological rationale for etiology-differentiated therapeutic approaches. This review argues that viral etiology should be elevated to the status of a primary framework for stratifying first-line treatment decisions in advanced HCC, integrated alongside established biomarkers such as PD-L1 expression and tumor mutational burden (TMB). We synthesize the current evidence linking viral etiology to TIME characteristics and differential treatment outcomes, propose a TIME-etiology clinical decision framework, examine safety considerations across etiologic subgroups, and outline critical directions for future research, including etiology-enriched trial designs, novel bispecific antibodies, antibody-drug conjugates (ADCs), and combination radiomics strategies.
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