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Given the critical role of CD8<jats:sup>+<\/jats:sup> T cells as antiviral effectors, we investigated their changes during FC to identify novel predictive markers of treatment efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We enrolled CHB patients with serum HBsAg levels &lt;\u20093000\u2009IU\/mL in a discovery cohort and collected their peripheral blood mononuclear cells after PEG\u2010IFN\u2010\u03b1 therapy. We used single\u2010cell transcriptome profiling coupled with T cell receptor (TCR) sequencing and flow cytometry to assess CD8<jats:sup>+<\/jats:sup> T cell immune characteristics. Findings were validated longitudinally by flow cytometry in an independent cohort receiving PEG\u2010IFN\u2010\u03b1 therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In FC patients, CD8<jats:sup>+<\/jats:sup> T cell subsets exhibited distinct transcriptional profiles. c04 (Temra\/Teff) and c06 (proliferating T) showed significant clonal expansion compared to non\u2010FC patients. CD300A expression was highly enriched in FC cells, correlating with cytotoxicity\u2010related gene signatures (e.g., <jats:italic>GZMB<\/jats:italic>, <jats:italic>GNLY<\/jats:italic>, <jats:italic>PRF1<\/jats:italic>). CD300A<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells demonstrated greater clonal expansion, enhanced antigen reactivity and a transcriptional network driven by <jats:italic>TBX21<\/jats:italic> and <jats:italic>EOMES<\/jats:italic>, with enrichment of HBV\u2010specific CD8<jats:sup>+<\/jats:sup> T cells. Longitudinal validation confirmed that baseline CD300A<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells, particularly non\u2010naive subsets, were associated with greater HBsAg decline and earlier FC, independent of baseline HBsAg levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CD300A<jats:sup>+<\/jats:sup> CD8<jats:sup>+<\/jats:sup> T cells are enriched in patients achieving FC during PEG\u2010IFN\u2010\u03b1 therapy, exhibiting robust clonal expansion, enhanced cytotoxicity and HBV antigen specificity. These cells may serve as potential biomarkers for treatment response to improve FC rates in CHB therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.70214","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T06:00:34Z","timestamp":1748844034000},"page":"512-525","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>CD300A<\/scp><sup>+<\/sup><scp>CD8<\/scp><sup>+<\/sup> T Cells as Predictive Biomarkers for Achieving Functional Cure in Chronic Hepatitis B Patients Undergoing Pegylated Interferon\u2010Alpha Therapy"],"prefix":"10.1111","volume":"62","author":[{"given":"Peng","family":"Zhang","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Senior Department of Infectious Diseases The Fifth Medical Center of Chinese PLA General Hospital  Beijing 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