Prospects for leveraging knowledge on ISG and NF-kB effector functions into anti-HBV therapies.

Chronic hepatitis B virus (HBV) infection affects nearly 300 million people worldwide and remains a leading cause of liver cirrhosis and hepatocellular carcinoma. Although current therapies, including interferon-α and nucleos(t)ide analogs, can suppress viral replication, they rarely achieve a functional or sterilizing cure, largely due to the persistence of covalently closed circular DNA (cccDNA) and profound immune dysfunction. Accumulating evidence indicates that noncytopathic immune mechanisms, particularly those mediated by interferons (IFNs) and inflammatory cytokines, are important to viral control. Interferon-stimulated genes (ISGs) and the nuclear factor-κB (NF-κB) signaling pathway together orchestrate a broad antiviral and immunomodulatory network that targets multiple stages of the HBV life cycle while shaping innate and adaptive immune responses. In this review, we comprehensively summarize current knowledge on how ISGs and NF-κB signaling restrict the life cycle of HBV infection. We further discuss the immunomodulatory roles of these pathways in reinforcing innate immune sensing, cytokine production, macrophage polarization, and T cell differentiation and function, all of which are critical determinants of HBV persistence versus clearance. Finally, we review emerging immunomodulatory strategies under preclinical and clinical development that exploit ISGs, pattern-recognition receptors, and NF-κB related pathways, and highlight the challenges and opportunities in translating these insights into curative therapies. Collectively, this review underscores the central role of ISGs and NF-κB signaling as both antiviral effectors and therapeutic targets, providing a conceptual framework for the development of next-generation immunotherapies aimed at curing chronic HBV infection.