Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Summary

This review article addresses an important and emerging area in cancer immunotherapy, namely viral mimicry and its therapeutic potential. The review is extensive and covers a wide range of topics from mechanistic insights to clinical applications. However, in its current form, the manuscript has several issues related to organization, redundancy, and lack of critical analysis that should be addressed.

Major concerns

1. Overly descriptive and not sufficiently critical

• The manuscript reads more like a compilation of studies rather than a critical review.
• Authors describe multiple mechanisms and therapies, but there is limited discussion on limitations, conflicting findings, or failures in the field.
• For example, issues like chronic IFN signaling leading to immune exhaustion or resistance are mentioned but not discussed in depth.

2. Redundancy throughout the manuscript

• Interferon signaling pathways are repeatedly explained across multiple sections (Sections 2, 3, and 4).
• This repetition reduces readability and gives an impression of lack of editing.
• Authors should consolidate these sections instead of repeating similar concepts.

3. Poor flow between sections

• The transition between mechanistic sections and therapeutic applications is not very smooth.
• Particularly, the CAR-T/CAR-NK section appears somewhat detached and not well integrated with viral mimicry mechanisms.

4. Clinical section lacks depth

• Although clinical trials are summarized, the discussion is mostly descriptive.
• There is no strong attempt to interpret why outcomes vary between tumor types or patient populations.
• The manuscript would benefit from highlighting key challenges in clinical translation.

5. Length and density

• The manuscript is unnecessarily long in certain sections, especially Section 3.
• Some paragraphs are too dense and could be shortened without losing content.

Minor concerns

• Typographical errors are present (e.g., “viral mimciry”).
• Some sentences are overly long and difficult to follow.
• Abbreviation usage is excessive in some parts.
• Figures are useful but sometimes redundant with the text.

Overall recommendation

Good manuscript but needs some revision for clarity and balance. The topic is relevant and the manuscript has potential, but requires major revision to improve clarity, reduce redundancy, and include more critical analysis.

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

1. The review thoroughly describes molecular mechanisms of viral mimicry but lacks a detailed discussion on how viral mimicry-inducing agents can be efficiently delivered to tumors in vivo. From a cancer therapy perspective, it would be valuable to discuss delivery platforms such as nanoparticles, viral vectors, lipid nanoparticles, or tumor-targeted delivery systems that can spatially restrict activation of nucleic acid sensing pathways.
2. Although the concept of viral mimicry is discussed mechanistically, the manuscript does not sufficiently explore virus-inspired therapeutic engineering, such as synthetic viral RNA/DNA mimetics, self-amplifying RNA systems, or engineered viral-like particles that could activate innate immune pathways in a controlled manner.
3. Activation of interferon signaling and innate immune sensors may cause systemic inflammation. The review acknowledges this challenge but does not sufficiently discuss strategies to improve tumor specificity, such as tumor-targeted promoters, conditional activation systems, or local delivery approaches.
4. The manuscript briefly mentions CAR-T and NK cell therapies, but the discussion remains relatively superficial. A more detailed analysis of how viral mimicry could synergize with adoptive cell therapies, TCR-T therapies, or neoantigen vaccines would enhance the translational perspective.
5. The manuscript summarizes biomarkers associated with viral mimicry activation (e.g., ERV transcripts, IFN signatures) , but does not provide a critical discussion on how these biomarkers could be used for patient stratification or therapeutic monitoring in clinical trials.
6. Given the role of dsRNA in triggering antiviral responses, the manuscript should discuss emerging RNA therapeutics, including synthetic dsRNA, self-replicating RNA, or CRISPR-based approaches to induce endogenous retroelement activation.

Author Response

Please see attachment. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Immune checkpoint blockade (ICB) therapy has reshaped the cancer treatment landscape. However, the number of patients who achieve durable responses is limited, and many patients experience immune-related adverse events. Thus, developing complementary strategies that enhance ICB efficacy while minimizing toxicity is an urgent priority. One emerging approach is coverting “immunologically cold” tumors into “immunologically hot” ones by inducing viral mimicry, in which aberrant accumulation of cytosolic nucleic acids is sensed by the sensors.

In this manuscript, Kirkland and colleagues summarize recent findings on how transcription of repetitive elements (REs) can be deregulated by epigenetic therapies and how viral mimicry is induced. The authors also discuss the impact of viral mimicry on the immune cells in the tumor microenvironment and describe clinical applications combining viral mimicry with ICB therapy, CAR-T and CAR-NK.

The review presents clear and highly informative content, which I find very attractive for a wide range of readers in Biomolecules. I have only a few minor comments;

 

Minor points:

 

1. It would be helpful if the components shown in Figure 1 were identified as specific cell types or ECM.

 

2. In the Conclusions, the authors mention “First, selective epigenetic modulation will be essential to avoid chronic IFN exposure while preserving the beneficial aspects of RE activation.” (Lines. 751-752). Because this point is critically important for overcoming resistance when exploiting viral mimicry therapeutically, it should be discussed in more detil earlier in the manuscript.

Author Response

Please see attachment. 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

 

The MS has improved significantly and addressed most of my major and the minor concerns. I recommend acceptance as per the editor’s discretion.

Reviewer 2 Report

Comments and Suggestions for Authors

I suggest accepting the revision in its present form.