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This study evaluated the dynamic changes in antibody-mediated NK cell responses and the involvement of distinct NK subsets across disease stages and during antiviral treatment.Methods: A T-cell receptor-like antibody specific for the HBV core 18\u201327 peptide (cTCRL-Ab) was used to determine the antibody-mediated effect of NK cells, and an array of NK cell surface markers were analyzed in cross-sectional and longitudinal cohorts of patients with chronic HBV infection. Single-cell RNA sequencing (scRNA-seq) was performed to identify the heterogeneity of NK subsets.Results: The cTCRL-Ab enabled the detection of NK cell cytolytic activity and IFN\u03b3 production. Notably, cTCRL-Ab-mediated NK cell responses were compromised in chronically HBV-infected patients, particularly in those receiving pegylated interferon-\u03b1 (Peg-IFN\u03b1), which was associated with the downregulation of CD16 expression. Correspondingly, Peg-IFN\u03b1 inhibited cTCRL-Ab-mediated NK cell function by reducing CD16 expression &lt;i&gt;in vitro&lt;\/i&gt;. scRNA-seq revealed that CD16 downregulation occurred mainly within a dysfunctional CD16hi NK subset exhibiting exhaustion properties. In contrast, an activated CD16&lt;sup&gt;hi&lt;\/sup&gt;NK subpopulation (CX3CR1\u207aKLRC2&lt;sup&gt;\u2013&lt;\/sup&gt;CD16&lt;sup&gt;hi&lt;\/sup&gt;) with high cytotoxicity was enriched in patients who experienced favorable treatment responses. Furthermore, the intrahepatic CX3CR1&lt;sup&gt;+&lt;\/sup&gt;KLRC2&lt;sup&gt;\u2013&lt;\/sup&gt;CD16&lt;sup&gt;hi&lt;\/sup&gt; subset tended to exhibit functional restoration in HBsAg-loss individuals.Conclusions: Our data contribute to the understanding of antibody-mediated responses of NK cells in chronic HBV infection, and highlight a previously unappreciated functional CX3CR1&lt;sup&gt;+&lt;\/sup&gt;KLRC2&lt;sup&gt;\u2013&lt;\/sup&gt;CD16&lt;sup&gt;hi&lt;\/sup&gt;NK subset as a potential therapeutic target.<\/jats:p>","DOI":"10.3350\/cmh.2025.0842","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T07:15:32Z","timestamp":1766128532000},"page":"683-705","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dissecting antibody-mediated natural killer cell effects reveals a cytotoxic CX3CR1+KLRC2\u2013CD16hi subset linked to hepatitis B virus 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