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Functional cure, defined as hepatitis B surface antigen seroclearance with unquantifiable HBV DNA at 24 weeks off treatment, is a desirable endpoint in the treatment of CHB, yet challenging to achieve. Given the limitations of current therapies including nucleos(t)ide analogues and pegylated interferon alpha, novel agents targeting functional cure are emerging. As hepatitis B virus (HBV) is a non-cytolytic virus, liver damage stems from the host immune response towards HBV-infected cells. The innate immune response during the initial phase of HBV infection is crucial in establishing an adequate level of immunity against the virus. However, HBV adopts various mechanisms to evade the host\u2019s innate immunity, partly contributing to the chronicity of infection. This article provides a comprehensive review on how the HBV life cycle interacts with the host\u2019s innate immune system. The latest evidence of novel agents targeting the innate immunity will also be covered. Retinoic acid inducible gene I agonists, toll-like receptor agonists, and interferons are therapies that target the HBV evasion strategies against host\u2019s innate immunity. While small interfering RNAs and antisense oligonucleotides are originally designed for antigen knockdown and reinvigoration of the adaptive immune response, they have also shown additional impacts on the innate immunity. With ongoing research and innovation in combination strategies, advancement in the management of CHB is anticipated in the future.<\/jats:p>","DOI":"10.3350\/cmh.2025.0935","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T07:19:36Z","timestamp":1762845576000},"page":"184-199","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Targeting the innate immune system in treating hepatitis B: prospects for functional cure"],"prefix":"10.3350","volume":"32","author":[{"given":"Karen Cheuk-Ying","family":"Ho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rex 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