Immune Checkpoint Inhibition Therapy Beyond the Tumor: Implications for Hepatitis B Virus in Hepatocellular Carcinoma

(See the Major Article by Ran et al on pages 1015–26.) Hepatitis B virus (HBV) remains one of the most widespread chronic viral infections worldwide. Despite effective viral suppression with nucleos(t)ide analogs (NAs), achieving cure or durable remission remains largely elusive. HBV continues to be a major contributor to global morbidity and mortality, accounting for ∼1.1 million deaths annually, predominantly from cirrhosis and hepatocellular carcinoma (HCC) [1]. This persistent disease burden reflects HBV's capacity to establish a long-lived viral reservoir, evade immune surveillance, and drive progressive liver injury. A central feature of HBV pathogenesis is the persistence of covalently closed circular DNA (cccDNA). cccDNA originates from relaxed circular DNA (rcDNA) within infectious virions; upon nuclear entry, rcDNA is converted to cccDNA, which resists immune clearance through epigenetic regulation, enabling lifelong persistence within hepatocytes [2, 3]. Conventional serological markers, including HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV DNA, fail to capture the complexity of these nuclear reservoir dynamics fully. In response, newer biomarkers such as pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) have emerged as tools to better reflect intrahepatic cccDNA transcriptional activity (see Figure 1) [4]. Although promising, these tests are still in the process of standardization, and they are not yet commercially available in most settings; as their utility remains largely investigational, additional validation is needed before clinical implementation.