CD300A+CD8+ T Cells as Predictive Biomarkers for Achieving Functional Cure in Chronic Hepatitis B Patients Undergoing Pegylated Interferon‐Alpha Therapy

ABSTRACT Background & Aims Pegylated interferon‐alpha (PEG‐IFN‐α) is the first choice for achieving functional cure (FC) in chronic hepatitis B (CHB), but only about 30% of patients achieve this outcome within a defined treatment duration. Given the critical role of CD8 + T cells as antiviral effectors, we investigated their changes during FC to identify novel predictive markers of treatment efficacy. Methods We enrolled CHB patients with serum HBsAg levels < 3000 IU/mL in a discovery cohort and collected their peripheral blood mononuclear cells after PEG‐IFN‐α therapy. We used single‐cell transcriptome profiling coupled with T cell receptor (TCR) sequencing and flow cytometry to assess CD8 + T cell immune characteristics. Findings were validated longitudinally by flow cytometry in an independent cohort receiving PEG‐IFN‐α therapy. Results In FC patients, CD8 + T cell subsets exhibited distinct transcriptional profiles. c04 (Temra/Teff) and c06 (proliferating T) showed significant clonal expansion compared to non‐FC patients. CD300A expression was highly enriched in FC cells, correlating with cytotoxicity‐related gene signatures (e.g., GZMB , GNLY , PRF1 ). CD300A + CD8 + T cells demonstrated greater clonal expansion, enhanced antigen reactivity and a transcriptional network driven by TBX21 and EOMES , with enrichment of HBV‐specific CD8 + T cells. Longitudinal validation confirmed that baseline CD300A + CD8 + T cells, particularly non‐naive subsets, were associated with greater HBsAg decline and earlier FC, independent of baseline HBsAg levels. Conclusions CD300A + CD8 + T cells are enriched in patients achieving FC during PEG‐IFN‐α 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.