Immunologic Drivers and Restraints in Colitis-Associated Colorectal Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This article systematically reviews the dual role of immune factors in colitis-associated colorectal cancer (CAC), presenting a topic of clinical significance with a complete structure and abundant literature. The overall quality is good. The following 7 suggestions for revision are proposed:
1. The term "immune cell plasticity" is mentioned multiple times in the text, but no clear definition is given for the first occurrence. It is suggested to provide a brief definition in the introduction or relevant sections.
2. TLR4 promotes cancer, while TLR3/TLR13 inhibits cancer. The text only lists the phenomena but does not deeply explain the differences in pathways and temporal and spatial specificity mechanisms. It is recommended to strengthen the discussion of mechanism comparison.
3. The clinical transformation part is thin. The conclusion mentions biomarkers and targeted therapy, but does not sort out the ongoing clinical progress and candidate targets. It is suggested to add 1-2 paragraphs of clinical transformation outlook.
4. The mechanisms related to macrophage polarization and cytokines refer to literature from 2008 to 2011. It is recommended to update the research in the past 5 years to improve timeliness.
5. The discussion on neutrophil extracellular traps (NETs) is insufficient. The role of NETs in CAC is only briefly mentioned, lacking key mechanisms and model evidence. It is recommended to appropriately expand or clearly explain the research limitations.
6. Some long sentences are overly lengthy and the logic is slightly confusing. The transition between Section 6 and Section 7 is abrupt. It is suggested to simplify the sentence structure and smooth the paragraph connection.
7. Immune cells and cytokines have complex functions, including both tumor-promoting and tumor-inhibiting effects. It is recommended to add a table to categorically summarize the core immune components, functions, and pathways for easier reading.

Author Response

Reviewer 1: We would like to thank the reviewer for his/her positive evaluation and helpful suggestions.

In response to the specific points raised by the reviewer:

1. The term "immune cell plasticity" is mentioned multiple times in the text, but no clear definition is given for the first occurrence. It is suggested to provide a brief definition in the introduction or relevant sections.

 Authors’ response: We have included the definition of immune cell plasticity as suggested.

2. TLR4 promotes cancer, while TLR3/TLR13 inhibits cancer. The text only lists the phenomena but does not deeply explain the differences in pathways and temporal and spatial specificity mechanisms. It is recommended to strengthen the discussion of mechanism comparison.

Authors’ response: we have expanded the TLR paragraph and add information about the TLR-driven signaling pathways.

3. The clinical transformation part is thin. The conclusion mentions biomarkers and targeted therapy, but does not sort out the ongoing clinical progress and candidate targets. It is suggested to add 1-2 paragraphs of clinical transformation outlook.

Authors’ response: we have added one paragraph (n.8) reporting the preclinical data on compounds used for targeting key molecules involved in colitis-associated colon cancer.

4. The mechanisms related to macrophage polarization and cytokines refer to literature from 2008 to 2011. It is recommended to update the research in the past 5 years to improve timeliness.

Authors’ response: we have updated the reference list with more recent studies.

5. The discussion on neutrophil extracellular traps (NETs) is insufficient. The role of NETs in CAC is only briefly mentioned, lacking key mechanisms and model evidence. It is recommended to appropriately expand or clearly explain the research limitations.

Authors’ response: we have expanded the NETs paragraph.

6. Some long sentences are overly lengthy and the logic is slightly confusing. The transition between Section 6 and Section 7 is abrupt. It is suggested to simplify the sentence structure and smooth the paragraph connection.

Authors’ response: we have revised the text and made the requested changes.

7. Immune cells and cytokines have complex functions, including both tumor-promoting and tumor-inhibiting effects. It is recommended to add a table to categorically summarize the core immune components, functions, and pathways for easier reading.

Authors’ response: we have added the requested table

Reviewer 2 Report

Comments and Suggestions for Authors

1. The topic of immune regulation in colitis-associated colorectal cancer (CAC) is highly relevant; however, the manuscript would benefit from more clearly highlighting its novelty compared with previously published reviews on the same topic. The authors should explicitly state what new perspectives or synthesis this review contributes to the existing literature.
2. While the manuscript provides a comprehensive overview of immune mechanisms involved in CAC, the structure could be improved. The transitions between sections discussing innate and adaptive immunity are somewhat abrupt. A clearer organizational framework with subheadings would improve readability.
3. Several important studies published in the past 3–4 years addressing immune checkpoint pathways, microbiota-immune interactions, and cytokine signaling in CAC are not sufficiently discussed. Including more recent references would strengthen the scientific relevance of the review.
4. The manuscript briefly mentions microbial signals in relation to Toll-like receptor activation, but the broader role of the gut microbiota in modulating immune responses and tumorigenesis in CAC deserves more detailed discussion.
5. The review provides a descriptive summary of immune cell populations involved in CAC but could benefit from deeper mechanistic explanations. In particular, signaling pathways such as NF-κB, STAT3, and IL-6 signaling that link chronic inflammation to tumorigenesis should be discussed in greater detail.
6. The concept of immune cells exerting both tumor-promoting and anti-tumor effects is an important theme of the manuscript. However, this duality could be presented more systematically, possibly through a comparative table summarizing immune cell subsets and their contrasting roles in CAC.
7. The manuscript would benefit from the inclusion of schematic figures illustrating the interplay between immune cells, cytokines, epithelial cells, and the tumor microenvironment in CAC. Visual summaries would greatly enhance comprehension for readers.
8. Although the manuscript discusses immunological mechanisms extensively, the translational implications remain somewhat limited. The authors should expand on potential clinical applications such as biomarkers for CAC risk prediction and immunomodulatory therapeutic strategies.
9. The emerging role of immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4 in colorectal cancer immunotherapy is not sufficiently addressed. Including discussion on how these pathways might influence CAC development or treatment would improve the clinical relevance of the review.
10. Overall, the manuscript is clearly written; however, minor grammatical inconsistencies and formatting issues are present. A careful editorial revision would improve readability and ensure consistency throughout the text.

Comments on the Quality of English Language

NA

Author Response

Reviewer 2: We would like to thank the reviewer for his/her positive evaluation and helpful suggestions.

In response to the specific points raised by the reviewer:

Comment 1. The topic of immune regulation in colitis-associated colorectal cancer (CAC) is highly relevant; however, the manuscript would benefit from more clearly highlighting its novelty compared with previously published reviews on the same topic. The authors should explicitly state what new perspectives or synthesis this review contributes to the existing literature.

Authors’ response: We have revised the text and made the requested changes.  

Comment 2. While the manuscript provides a comprehensive overview of immune mechanisms involved in CAC, the structure could be improved. The transitions between sections discussing innate and adaptive immunity are somewhat abrupt. A clearer organizational framework with subheadings would improve readability.

Authors’ response: We have revised the text and made the requested changes.  

Comment 3. Several important studies published in the past 3–4 years addressing immune checkpoint pathways, microbiota-immune interactions, and cytokine signaling in CAC are not sufficiently discussed. Including more recent references would strengthen the scientific relevance of the review.

Authors’ response: We have revised the text and made the requested changes. 

Comment 4. The manuscript briefly mentions microbial signals in relation to Toll-like receptor activation, but the broader role of the gut microbiota in modulating immune responses and tumorigenesis in CAC deserves more detailed discussion.

Authors’ response: We have expanded the paragraph relative to TLR by adding all the relevant data about the role of microbiota in the pathogenesis of colitis-associated colon cancer.

Comment 5. The review provides a descriptive summary of immune cell populations involved in CAC but could benefit from deeper mechanistic explanations. In particular, signaling pathways such as NF-κB, STAT3, and IL-6 signaling that link chronic inflammation to tumorigenesis should be discussed in greater detail.

Authors’ response: we have expanded the text and added information relative to the role of NF-kB, Stat3 and IL-6 signaling in colitis-associated colon cancer. As mentioned in the initial paragraphs, the description of the role of specific cytokines in the pathogenesis of colitis-associated colon cancer was beyond the scope of this article. 

Comment 6. The concept of immune cells exerting both tumor-promoting and anti-tumor effects is an important theme of the manuscript. However, this duality could be presented more systematically, possibly through a comparative table summarizing immune cell subsets and their contrasting roles in CAC.

Comment 7: The manuscript would benefit from the inclusion of schematic figures illustrating the interplay between immune cells, cytokines, epithelial cells, and the tumor microenvironment in CAC. Visual summaries would greatly enhance comprehension for readers.

Authors’ response: we thank the reviewer for this suggestion. However, we would like to point out that the manuscript already includes two figures and one table, and it is quite lengthy (over 36 pages). Therefore, we have decided not to include any additional figures or tables.

Comment 8. Although the manuscript discusses immunological mechanisms extensively, the translational implications remain somewhat limited. The authors should expand on potential clinical applications such as biomarkers for CAC risk prediction and immunomodulatory therapeutic strategies.

Authors’ response: we have added a paragraph relative to the preclinical work investigating the preventive/therapeutic effects of various compounds in colitis-associated colon cancer.

Comment 9. The emerging role of immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4 in colorectal cancer immunotherapy is not sufficiently addressed. Including discussion on how these pathways might influence CAC development or treatment would improve the clinical relevance of the review.

Authors’ response: In paragraph 8, we present evidence supporting the use of immune checkpoint inhibitors for treating specific subgroups of patients with sporadic colon cancer. We also highlight that these agents increase the risk of immune-mediated colitis, which suggests that they should not be considered part of the treatment options for colon cancer associated with inflammatory bowel disease

Comment 10. Overall, the manuscript is clearly written; however, minor grammatical inconsistencies and formatting issues are present. A careful editorial revision would improve readability and ensure consistency throughout the text.

Authors’ response: we have checked and made the requested changes. 

Reviewer 3 Report

Comments and Suggestions for Authors

The authors described that the inflammation in IBD showed the influences of inflammatory cells in context- and temporal-dependent fashion, resulting in pro-tumoral or anti-tumoral effects. The manuscript is well witten & organized with clear workflow. The concerns are as follows: 

1. It would be good to add the difference of incidence of cancer between the sporadic colorectal cancer and colitis-associated colorectal cancer as a number in the introduction.
2. Could you describe whick factors increase the incidence of cancer in the IBC patients in the introduction?
3. It would be good to include the description of eosinophils in the section of innate immunity.
4. It wound be good to create a table or figure showing the immunologic difference between sporadic colorectal cancer and CAC.
5. It is necessary to summerize the characteristics of the high-risk group of CAC in IBD patients in the conclusion.

Author Response

Reviewer 3: We would like to thank the reviewer for his/her positive evaluation and helpful suggestions.

In response to the specific points raised by the reviewer:

Comment 1. It would be good to add the difference of incidence of cancer between the sporadic colorectal cancer and colitis-associated colorectal cancer as a number in the introduction.

Authors’ response: in the introduction section, we reported the differences in incidence between colitis-associated colon cancer and sporadic colon cancer.

Comment 2. Could you describe whick factors increase the incidence of cancer in the IBC patients in the introduction?

Authors’ response: we have stated which factors enhance the risk of colon cancer in IBD patients.

Comment 3: It would be good to include the description of eosinophils in the section of innate immunity.

Authors’ response: we have expanded the paragraph on innate immune cells and added the data supporting the dual role of eosinophils in colitis-associated colon cancer.

Comment 4. It would be good to create a table or figure showing the immunologic difference between sporadic colorectal cancer and CAC.

Authors’ response: we thank the reviewer for this suggestion. However, we would like to point out that the manuscript already includes two figures and one table, and it is quite lengthy (over 36 pages). Therefore, we have decided not to include any additional figures or tables.

Comment 5. It is necessary to summerize the characteristics of the high-risk group of CAC in IBD patients in the conclusion.

Authors’ response: we have reported the characteristics of the high-risk group of CAC in IBD patients in the conclusion.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

No additional comments.