Dear Editor,
We sincerely thank Professor Wang and colleagues for their thoughtful and insightful commentary regarding our recent publication [
1]. We are grateful for their meticulous review of our work and their constructive feedback, which situates our findings within a more extensive conceptual and translational framework. We are pleased to respond to the key points raised.
Firstly, we fully agree with the authors’ interpretation that the phenotypic changes observed during pegylated interferon-α (Peg-IFNα) therapy are more appropriately understood as a process of immune remodeling rather than immune restoration. As highlighted in a recent study, the objective of current functional cure strategies is not to restore the immune system to a pre-infection naïve state. Rather, these strategies seek to direct the immune system towards a novel, functional equilibrium that can ensure sustained viral control [
2].
In our study, T-cell receptor-like antibody specific for hepatitis B virus (HBV) core 18-27 epitope (cTCRL-Ab) system was primarily employed as a mechanistic tool to interrogate antibody-mediated natural killer (NK) cell function. Our data indicated that while global CD16 expression is downregulated, a specialized elite subset (CX3CR1⁺KLRC2⁻CD-16
hi) is enriched in responders. We concur that relying on endogenous antibodies alone may be insufficient in this remodeled landscape. The proposal by Xu et al. [
3] to incorporate engineered high-affinity antibodies, such as cTCRLAb, is in alignment with recent advancements discussed in this journal. For instance, Wan et al. demonstrated that genetically modified, redirected T cells can effectively target HBV-related hepatocellular carcinoma (HCC) [
4].
Secondly, we acknowledge the emphasis on immune checkpoint constraints, particularly the role of NKG2A, in limiting therapeutic responses. Indeed, our single-cell analyses demonstrated that KLRC1 expression was increased within the CX3CR1⁺KLRC2⁻CD16
hi NK subset in non-complete responders, whereas this inhibitory signal was reduced in individuals achieving HBsAg loss. These observations suggest that, even within an otherwise cytotoxic and activated NK cell population, persistent inhibitory signaling may attenuate antiviral efficacy and contribute to treatment resistance. As the authors have indicated, the obstruction of the NKG2A-HLA-E axis has the potential to reinstate the functionality of NK cells and thereby facilitate the eradication of viral infections. Although our study was not designed to directly assess checkpoint blockade strategies, it is acknowledged that the combination of Peg-IFNα with inhibitory receptor targeting constitutes a rational and promising direction for future research. This perspective aligns with the prevailing consensus within the field. Chronic HBV infection is characterized by persistent immune exhaustion, which makes achieving a functional cure difficult with monotherapy and necessitates combined antiviral and immunomodulatory strategies [
5]. We concur with the prevailing perspective that combinatorial strategies are indispensable. Recent studies have also indicated that novel agents, such as capsid assembly modulators, may require pairing with immunomodulators to achieve optimal HBsAg loss [
6].
Thirdly, we acknowledge the important point raised regarding the distinction between causality and correlation. Our data demonstrate a strong association between enrichment of the CX3CR1⁺KLRC2⁻CD16
hi NK subset and favorable virological outcomes, including HBeAg seroconversion and HBsAg loss. To resolve these issues, longitudinal intrahepatic sampling and mechanistic studies in appropriate in vivo models are essential. We concur that such approaches are necessary to establish causality. To address this question, subsequent research could employ innovative monitoring technologies for conducting longitudinal studies. As previously mentioned, advanced liquid biopsy techniques are becoming increasingly important for monitoring disease progression and therapeutic response in liver diseases [
7].
In summary, we are grateful to Xu and colleagues for their constructive commentary, which underscores the broader implications of our findings. We concur with their assertion that our study underscores a transition from global NK cell activation to subpopulation-specific immune remodeling, a shift that carries significant ramifications for the design of effective therapeutic interventions. The identification of a cytotoxic CX3CR1⁺KLRC2⁻CD16hi NK subset associated with treatment response and functional cure provides a framework for future studies. These studies will integrate immune remodeling with targeted and combinatorial immunotherapeutic strategies to achieve durable control of chronic HBV infection.
FOOTNOTES
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Authors’ contributions
ZHJ, LBT, YHW, SHZ, YYL are responsible for manuscript preparation, concept synthesis and finalization. All authors read and approved the final manuscript.
-
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (82270647 and 82272314).
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Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
T-cell receptor-like antibody specific for HBV core 18-27 epitope
REFERENCES
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