CD161-lectin-like transcript 1 axis beyond programmed cell death protein 1 in hepatitis B virus-associated hepatocellular carcinoma

Abstract

Hepatitis B virus (HBV)-associated hepatocellular carcinoma develops in a chronically inflamed, tolerogenic liver microenvironment. In this setting, T-cell dysfunction limits the efficacy of programmed death-1 (PD-1) blockade. Emerging evidence from Liu et al published in the World Journal of Gastrointestinal Oncology suggests that CD161 may represent an additional inhibitory axis within exhausted CD8+ T cells that is not fully captured by the PD-1/programmed death ligand-1 pathway. In their study, CD161+CD8+ T cells were enriched in tumor tissue, and CD161 expression persisted even as PD-1+ compartments contracted after PD-1 inhibition, suggesting that CD161-mediated restraint may remain active under therapeutic pressure. Mechanistically, sustained engagement of the CD161-lectin-like transcript 1 interaction may impair T-cell effector function and contribute to adaptive immune resistance in the HBV-infected liver. These findings highlight the importance of protein-level assessment of CD161 and parallel evaluation with PD-1 to accurately characterize immune inhibition. Key knowledge gaps include the cellular source of lectin-like transcript 1 within the tumor microenvironment, the influence of ongoing HBV virological activity on CD161+ T-cell subsets, and the identification of clinically meaningful progression endpoints. In this editorial, we place these findings in mechanistic and translational context, highlighting the potential role of the CD161-lectin-like transcript 1 axis as a complementary pathway of immune resistance beyond PD-1 blockade. Collectively, the current evidence supports a cautious, hypothesis-driven translational strategy to evaluate combined modulation of the CD161 and PD-1 axes in carefully selected patients with HBV-associated hepatocellular carcinoma.

Keywords: CD161; Hepatocellular carcinoma; Hepatitis B virus; Immune resistance; T-cell exhaustion; Programmed death-1/programmed death ligand-1 resistance

Core Tip: In hepatitis B virus-associated hepatocellular carcinoma, CD161+CD8+ T cells are enriched in tumor tissue and may persist despite programmed death-1 blockade, suggesting that immune inhibition is not fully explained by the programmed death-1/programmed death ligand-1 axis alone. These observations raise the possibility that the CD161-lectin-like transcript 1 pathway represents a complementary mechanism of adaptive immune resistance. This editorial highlights the importance of protein-level CD161 assessment and discusses the translational relevance of this axis as a potential biomarker and therapeutic target for future investigation.