The Interplay Between Circadian Clocks and the Tumour Microenvironment in Breast Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review article is well written and on an important and relevant topic. 

Specific points.

1. The main focus is on breast cancer. Should it be reflected in the title and abstract, following the structure of the manuscript: breast cancer-circadian clock-breast cancer plus circadian clock? Otherwise, the title and abstract are read as too general, while the manuscript focuses on a specific group of cancers, and some information is not universal.

2. Figures are of good quality. Figure legends are detailed enough for accessibility.  

3. Figure 2. Font sizes are inconsistent for the text. Sometimes the text starts with a capital letter, sometimes not. Kindly consider making it more consistent. Applies to all the Figures when relevant. 

4. Lines 455-487. This paragraph is too long. Consider changing for more comfortable reading (shorten, split up). It is beneficial for the presentation of the manuscript to avoid long paragraphs. 

5. Lines 517-543. Long paragraph. Consider restructuring it.

6. Lines 544-570. Long paragraph.

7. Lines 590-619. Long paragraph.

8. Conclusions are too long, more like a concluding section than a sharp bullet point conclusion. Optionally, this section can be renamed or significantly shortened. 

Author Response

See Attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “The Interplay Between Circadian Clocks and the Tumour Microenvironment” by Finger et al. represents a compelling and well-structured review offering novel insights into the links between circadian clocks and TME in breast cancer. The authors provide a nuanced framework that enhances our understanding of the role of circadian clocks in pathogenesis of cancer integrating insights from mechanobiology, metabolism, immune regulation, and aging. This is a timely, informative, well-illustrated and well-articulated review.

 

Title:

• Since this review focuses on breast cancer, this should be reflected in its Title

 

Major comments:

• It is suggested that a Table summarizing studies on the impact of circadian clocks on TME in breast cancer is added
• A Figure highlighting TME-related circadian vulnerabilities that can be therapeutically exploitable should be added

 

Minor issues:

• Figure 2. Myosin instead of mysoin

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The review report “The Interplay Between Circadian Clocks and the Tumour Microenvironment” can be accepted after major revisions. My comment are listed below.

1. The manuscript primarily summarizes previously published studies without clearly highlighting its unique contribution or conceptual advancement beyond existing reviews on circadian regulation and the tumor microenvironment.
2. Although the interplay between circadian clocks and the tumor microenvironment is discussed, the manuscript lacks detailed mechanistic explanations, particularly regarding molecular signaling pathways and regulatory networks.
3. Most sections are descriptive rather than analytical. The authors should critically evaluate conflicting findings and identify knowledge gaps instead of only reporting prior work.
4. The structure of the manuscript appears fragmented, with some topics introduced abruptly. A clearer logical progression from circadian biology to tumor-specific implications would improve readability.
5. Please provide more schematic figures of the author’s version to describe the content of the review.
6. The manuscript briefly mentions therapeutic implications, but the clinical relevance—such as chronotherapy strategies, treatment timing, or patient outcomes—requires deeper discussion supported by recent studies.
7. Several references appear dated. Incorporating more studies from the last 2 to 3 years would strengthen the manuscript and reflect the rapidly evolving nature of this field.
8. Overgeneralization: Some statements regarding circadian disruption and cancer progression are too broad and would benefit from qualification or supporting evidence.
9. The future directions are somewhat generic. The authors should propose specific research questions, emerging technologies, or experimental approaches to guide the field forward.
10. Minor grammatical issues and repetitive explanations are present throughout the manuscript. I suggest the authors for careful proofreading and condensation of overlapping content are recommended to improve clarity and conciseness.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

1. Authors should include the Methodology parts: How many references were extracted? From what years to what years? How was it analyzed? (PRISMA, etc.) Please include this section in the manuscript.
2. This sentence looks incomplete” Cancer is currently understood as both a tissue and systemic disease, whose features change dramatically over time and spac
3. There appears to be a mismatch between the title and the stated objectives. The title focuses on circadian clocks and the tumour microenvironment, while the objectives emphasize cancer hallmarks and breast cancer more broadly. Please consider aligning the objectives more closely with the title, or revising the title to better reflect the broader scope of the review.
4. Line-102-line 122: For classification purposes, this information would be clearer and more reader-friendly if presented as a concise table summarizing ER, PR, and HER2 status across the major breast cancer subtypes rather than in paragraph form.
5. The statement linking obesity to TNBC risk in pre-menopausal women would benefit from further elaboration. The authors are encouraged to briefly describe the underlying non-hormonal mechanisms (e.g., immune dysregulation, chronic inflammation, insulin resistance, and metabolic alterations) to better explain how obesity contributes to increased breast cancer risk in this population.
6. Please briefly define “E-box” at first mention in main text and clarify its functional relevance to breast cancer development.
7. The authors may briefly indicate the location of the master clock and note the presence of peripheral clocks in specific tissues for better physiological context.
8. The manuscript does not clearly discuss key mechanisms such as metabolic alterations, immune dysregulation, and extracellular matrix (ECM) remodeling in relation to circadian clock–mediated breast cancer development. A brief, structured mention of these factors would improve clarity and strengthen the mechanistic understanding.
9. The conclusion appropriately outlines several important open questions; however, the future perspectives, limitations and significance would benefit from clearer structuring.

 

 

 

Comments on the Quality of English Language

Please check the typological errors and syntax  part.

Author Response

See the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

I accept it now.