Mechanisms of Immune Evasion in Chronic Hepatitis B Infection: The Role of Cytokines and Immune Cells

Background : Chronic hepatitis B (CHB) affects approximately 296 million people globally and is a major cause of liver fibrosis and hepatocellular carcinoma. CHB is characterized by immune dysfunction, including impaired innate responses, dysregulated cytokine signalling, and exhausted T/NK cells regulated via PD-1/PD-L1 checkpoints. The precise relationship between cytokine dysregulation and cellular exhaustion within the human liver remains poorly understood. Objective : To use publicly available human liver transcriptomic data to characterize CHB immune-evasion mechanisms and to examine the association between immune recognition, antigen presentation, checkpoint-pathway activation, and the cytokine microenvironment (e.g., IL-10, TGF-β, and interferon α/γ) and T/NK-cell functional states across disease stages. Methods : Liver biopsy transcriptomes from CHB patients (n = 120) and controls (n = 25; 145 samples total) across three public datasets (GSE84044, GSE83898, and GSE230397) were normalized and integrated, then subjected to immune-cell deconvolution (CIBERSORTx, EPIC, xCell). Known HBV immune-evasion mechanisms (RIG-I/MDA5 inhibition, HBsAg/HBeAg-mediated suppression), differential expression, gene-set enrichment, cytokine-module scoring, and checkpoint ligand-receptor co-expression were assessed. Results : CHB livers showed reduced antiviral/ISG signatures, increased IL-10/TGF-β module activity, and altered monocyte/macrophage phenotypes relative to controls. Elevated PD-L1 on liver and myeloid cells co-occurred, at the transcriptional level, with markers of exhausted T/NK populations expressing PD-1, LAG-3, and CD94, together with reduced cytotoxic CD8+ effector signatures and increased Treg signatures. PD-L1 upregulation was also associated with HBx- and polymerase-related transcriptional programs. Conclusions : CHB immune escape is associated with a self-reinforcing cytokine-checkpoint transcriptional program in which viral antigen exposure correlates with suppressed innate antiviral signalling and an IL-10/TGF-β-dominated microenvironment, alongside a T/NK exhaustion signature. Candidate markers – PD-L1, the IL10/TGFB1 module, and the CD94/HLA-E axis – may help stratify patients and are proposed as hypothesis-generating targets for future, independently validated combination immunotherapy strategies pairing checkpoint and cytokine-pathway blockade.