The Role of Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in the Tumor Microenvironment and Their Impact on Ovarian Cancer Survival and Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this manuscript entitled: “The Role of Fibroblasts and Macrophages in the Tumor Microenvironment and Their Impact on Ovarian Cancer Survival and Therapy.”

This work is intended to provide a comprehensive and up -to -date overview of the role of cancer - associated fibroblasts (CAFs) in the ovarian cancer tumor microenvironment, highlighting their origins, heterogeneity, and contributions to tumor progression, therapeutic resistance, and potential treatment strategies. The manuscript addresses an important and timely topic and is generally well written. However, several scientific, structural, and stylistic issues should be addressed before the manuscript can be considered for publication. My comments are outlined below.

1. Introduction

The introduction contains some repetition, particularly regarding the role of the tumor microenvironment (TME) in therapy resistance. For example, lines 65 - 69 repeat concepts already stated in lines 57 - 60. I recommend refining the structure this section by merging overlapping statements on therapy resistance and TMEs with limited immune infiltration to improve clarity and narrative flow.

2. Figure 1 (CAFs and TAMs in the TME)

Figure 1 is visually busy and lacks consistency. In addition, the adipocyte is shown twice without a clear rationale. I suggest redesigning the figure using a more organized layout, for example by grouping pathways according to functional categories (e.g., ECM remodeling, immune modulation, tumor -cell signaling, therapy resistance) and positioning them in clearly separated panels or regions. A more linear or modular schematic may be more effective.

3. Section 3.1. Origins and Heterogeneity of CAFs

Line 136 repeats the phrase “Advanced technologies have revealed,” which already appears in the previous sentence. The description of CAF subtypes (apCAFs, iCAFs, and myCAFs) is generally accurate but incomplete, as it does not reference ECM-associated CAF populations reported in ovarian tumors. Including these would strengthen this section.

4. Section 3.4. CAF Plasticity and Transcriptional Regulation in Epithelial Ovarian Cancer

The statement that TCF21 “promotes a tumor-supportive phenotype” (lines 192–193) is not consistent with the broader literature, in which TCF21 is widely described as a tumor-suppressive transcription factor, and its loss - rather than activation- has been associated with CAF activation. This represents a significant scientific inaccuracy. Please provide specific evidence supporting a tumor -promoting role for TCF21 in epithelial ovarian cancer, or revise the text to reflect current understanding.

In addition, this section would benefit from discussion of other transcriptional regulators known to influence CAF biology (e.g., TWIST1, YAP/TAZ). Including at least one additional regulator would improve the completeness of the review.

5. Figure 2 (CAF Signaling Pathways)

In Figure 2, the visual representation of tumor cells and CAFs is confusing, and the signaling pathways appear scattered rather than organized by functional categories (e.g., immune modulation, ECM remodeling, therapy resistance). Some pathways discussed in the text are also difficult to identify visually. I recommend restructuring the figure so that CAF- derived signals, CAFs themselves, and tumor - cell pathway activation are clearly separated and aligned with the manuscript narrative.

6. Section 3.5. CAF Risk Scores

There is a wording error in line 210 (“in EO” should be “in EOC”). Additionally, the section does not clearly indicate whether the CAF risk score has been validated in clinical cohorts, nor whether it is prognostic, predictive, or both. Please clarify these points.

7. TAM Sections (Sections 5.0 - 6.0)

These sections are detailed and generally scientifically sound, with appropriate referencing. Figures 4 and 5 are clear overall; however, Figure 4 is oversimplified. In particular, the beginning of the figure suggests a linear differentiation of monocytes into M1 or M2 macrophages, which does not reflect the known heterogeneity and plasticity of TAMs in ovarian cancer.

In addition, the statement in line 293 that M2 TAMs “represent the most dominant immune cell population” should be qualified (e.g., “often” or “in many cases”), as this is not consistently observed across datasets.

8. Autophagy in CAFs (Section 3.3)

I would like to request clarification and correction of the section discussing autophagy in CAFs. The manuscript states that autophagy inhibition promotes CAF transformation, whereas autophagy induction reverses CAF activation and restores fibroblast quiescence. However, current evidence indicates that the relationship between autophagy and CAF activation is highly context dependent. In many tumor types, including ovarian cancer, autophagy can support CAF survival, cytokine secretion, ECM remodeling, and pro - tumorigenic activity, while autophagy inhibition can reduce CAF activation. Please clarify which specific studies support the unidirectional interpretation presented in the manuscript. If these findings are limited to specific experimental models, the text should be revised to emphasize the dual and context - dependent role of autophagy in CAF biology. Moreover, this section lacks essential references and appears scientifically incomplete. According to the established framework described by Galluzzi, Kroemer autophagy is a complex and context - dependent process with sometimes different roles in stromal biology. I recommend revising this section accordingly and citing foundational autophagy guidelines or key works by Galluzzi et al. to ensure scientific accuracy.

9. Conclusion

The conclusion is strong and well written but repeats several points already discussed earlier in the manuscript. Consider streamlining this section to focus on key concepts, therapeutic implications, and future directions for targeting CAFs and TAMs.

The manuscript has strong potential but requires revision to address issues related to scientific accuracy (particularly regarding TCF21 and autophagy), figure clarity, overlap, and mechanistic precision.

Author Response

Responses to comments from Reviewer 1:

“This work is intended to provide a comprehensive and up -to -date overview of the role of cancer - associated fibroblasts (CAFs) in the ovarian cancer tumor microenvironment, highlighting their origins, heterogeneity, and contributions to tumor progression, therapeutic resistance, and potential treatment strategies. The manuscript addresses an important and timely topic and is generally well written. However, several scientific, structural, and stylistic issues should be addressed before the manuscript can be considered for publication. My comments are outlined below.”

Comment 1: “Introduction. The introduction contains some repetition, particularly regarding the role of the tumor microenvironment (TME) in therapy resistance. For example, lines 65 - 69 repeat concepts already stated in lines 57 - 60. I recommend refining the structure in this section by merging overlapping statements on therapy resistance and TMEs with limited immune infiltration to improve clarity and narrative flow.”

Response: We thank the reviewer for their time, careful examination of our manuscript, and feedback. We have re-written this portion of the introduction, combining the overview of CAFs, TAMs, and the TME, along with statements on limited immune cell presence and therapeutic resistance, in order to minimize repetition and improve flow.  

Comment 2: “Figure 1 (CAFs and TAMs in the TME). Figure 1 is visually busy and lacks consistency. Additionally, the adipocyte is depicted twice without a clear rationale. I suggest redesigning the figure using a more organized layout, for example, by grouping pathways according to functional categories (e.g., ECM remodeling, immune modulation, tumor-cell signaling, therapy resistance) and positioning them in clearly separated panels or regions. A more linear or modular schematic may be more effective.”

Response: To avoid repetition and provide a comprehensive depiction of CAFs and TAMs in the ovarian cancer TME, we have combined the overview of CAFs and TAMs (Figure 1) and the CAF signaling pathways (Figure 2) into a single figure: Figure 1. Signaling pathways have been organized accordingly.

Comment 3: “Section 3.1”. Origins and Heterogeneity of CAFs. Line 136 repeats the phrase “Advanced technologies have been revealed,” which already appears in the previous sentence. The description of CAF subtypes (apCAFs, iCAFs, and myCAFs) is generally accurate but incomplete, as it does not reference ECM-associated CAF populations reported in ovarian tumors. Including these would strengthen this section.”

Response: We removed this phrase from Section 3.1. sentence 4 to avoid repetition. We also added additional information on the role that ECM-associated CAF populations play in ovarian cancer with appropriate sources.

Comment 4: “Section 3.4. CAF Plasticity and Transcriptional Regulation in Epithelial Ovarian Cancer. The statement that TCF21 “promotes a tumor-supportive phenotype” (lines 192–193) is not consistent with the broader literature, in which TCF21 is widely described as a tumor-suppressive transcription factor, and its loss - rather than activation- has been associated with CAF activation. This represents significant scientific inaccuracy. Please provide specific evidence supporting a tumor-promoting role for TCF21 in epithelial ovarian cancer or revise the text to reflect current understanding.

 In addition, this section would benefit from discussion of other transcriptional regulators known to influence CAF biology (e.g., TWIST1, YAP/TAZ). Including at least one additional regulator would improve the completeness of the review.”

Response: We apologize for this error. The sentence has been corrected to state: “TCF21 influences fibroblast differentiation and has been implicated in promoting a tumor-suppressive phenotype (Hussain, 2020).” and an additional reference was added for completeness. We also included the transcriptional regulator SMAD2/3/4 due to its role in CAF differentiation, ECM remodeling, and immune exclusion.

Comment 5: “Figure 2 (CAF Signaling Pathways). In Figure 2, the visual representation of tumor cells and CAFs is confusing, and the signaling pathways appear scattered rather than organized by functional categories (e.g., immune modulation, ECM remodeling, therapy resistance). Some pathways discussed in the text are also difficult to identify visually. I recommend restructuring the figure so that CAF- derived signals, CAFs themselves, and tumor-cell pathway activation are clearly separated and aligned with the manuscript narrative.”

Response: We combined the overview of CAFs and TAMs (Figure 1) and the CAF signaling pathways (Figure 2) into a single figure: Figure 1. Signaling pathways have been organized according to function.  

Comment 6: “Section 3.5. CAF Risk Scores. There is a wording error in line 210 (“in EO” should be “in EOC”).

Additionally, the section does not clearly indicate whether the CAF risk score has been validated in clinical cohorts, nor whether it is prognostic, predictive, or both. Please clarify these points.”

Response: We corrected the misspelling to “EOC”. Additionally, I have edited section 3.5 to include that this study validates its findings and the use of the CAF risk score on ovarian cancer prognosis in clinical cohorts. 

Comment 7: TAM Sections (Sections 5.0 - 6.0). These sections are detailed and generally scientifically sound, with appropriate referencing. Figures 4 and 5 are clear overall; however, Figure 4 is oversimplified. In particular, the beginning of the figure suggests a linear differentiation of monocytes into M1 or M2 macrophages, which does not reflect the known heterogeneity and plasticity of TAMs in ovarian cancer.

In addition, the statement in line 293 that M2 TAMs “represent the most dominant immune cell population” should be qualified (e.g., “often” or “in many cases”), as this is not consistently observed across datasets.

Response: We thank the reviewer for their recommendations. We have revised Figure 4, including a more accurate representation of the differentiation from monocytes and tissue-resident macrophages into TAMs, considering heterogeneity and plasticity.

Additionally, we rephrased the statement to: “In many cases, they (TAMs) represent the most abundant immune cell population within the ovarian cancer TME”.

Comment 8: “Autophagy in CAFs (Section 3.3). I would like to request clarification and correction of the section discussing autophagy in CAFs. The manuscript states that autophagy inhibition promotes CAF transformation, whereas autophagy induction reverses CAF activation and restores fibroblast quiescence. However, current evidence indicates that the relationship between autophagy and CAF activation is highly context dependent. In many tumor types, including ovarian cancer, autophagy can support CAF survival, cytokine secretion, ECM remodeling, and pro - tumorigenic activity, while autophagy inhibition can reduce CAF activation. Please clarify which specific studies support the unidirectional interpretation presented in the manuscript. If these findings are limited to specific experimental models, the text should be revised to emphasize the dual and context-dependent role of autophagy in CAF biology. Moreover, this section lacks essential references and appears scientifically incomplete. According to the established framework described by Galluzzi, Kroemer autophagy is a complex and context - dependent process with sometimes different roles in stromal biology. I recommend revising this section accordingly and citing foundational autophagy guidelines or key works by Galluzzi et al. to ensure scientific accuracy.”

Response:  Thank you for reviewing and bringing this to my attention. I have done further research on this section of the review article and found that many current literatures discuss similar viewpoints from your comment. I have read and revised this section accordingly to make sure the information was relevant and accurate.

Comment 9: Conclusion. The conclusion is strong and well written but repeats several points already discussed earlier in the manuscript. Consider streamlining this section to focus on key concepts, therapeutic implications, and future directions for targeting CAFs and TAMs.

Response: Thank you for suggestions; we have corrected the conclusion section accordingly.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is generally well written and well organized. However, the review predominantly addresses the biology and underlying mechanisms/pathways of CAFs and TAMs rather than their impact on survival and therapeutic outcomes. If the authors wish to adhere to this conceptual focus, I suggest placing greater emphasis on studies that have evaluated therapeutic strategies targeting CAFs and TAMs and have reported corresponding results. This should be supported by summary tables compiling the relevant literature, including therapeutic approach, target cell population, key outcomes, and identified weaknesses. The currently provided Tables 1 and 2 are poorly informative and should be revised or expanded to better support this purpose. Additionally, when discussing survival analyses in correlation with CAFs and TAMs, it is essential to clearly specify the methods used for their evaluation and quantification. 

Moreover, in ovarian carcinoma, ascitic fluid is a very common phenomenon, especially in advanced stages, and it is important to highlight that investigating CAFs and TAMs in this context is of great value for understanding their role and potential impact on survival.

Separate paragraph on challenges and future goals might improve the impact of the review analysis.

Minor comments:

In the Introduction section, I suggest that at line 60, the description of the TME, including CAFs and TAMs, be presented in a more fluid and cohesive way. The current sections on CAFs (lines 70–78) and TAMs (lines 85–100) feel somewhat disjointed, as similar content is repeated within their respective sections. Consider reorganizing to avoid repetition and improve clarity. The Introduction should conclude clearly with the objective of the review.

Figure 2 fits more appropriately in Section 3.2 rather than 3.1; please revise accordingly. I also suggest avoiding titles within the figures themselves, as all information should be provided in the figure legends. Similarly, any notes such as “created with BioRender” should appear only in the legend, not on the figure. Moreover, please correct all figures, as they appear distorted, and provide them in their original size with proper aspect ratios.

Please define all abbreviations accordingly (lines 136, 139, 191, 209, 210, 227, 228, 251, 245, 428, ...). Also explain all abbreviations under tables and images accordingly. 

Line 184: avoid bold

Lines 185-186: rather express as it would be interesting to investigate... instead of another analysis could examine...

Lines 217-220: reference is missing

Line 240: ex-tracellular change to extracellular

Line 245: avoid capital first letters such us Ovarian Cancer

Author Response

Response to comments from Reviewer 2:

Comment 1: “The manuscript is generally well written and well organized. However, the review predominantly addresses the biology and underlying mechanisms/pathways of CAFs and TAMs rather than their impact on survival and therapeutic outcomes. If the authors wish to adhere to this conceptual focus, I suggest placing greater emphasis on studies that have evaluated therapeutic strategies targeting CAFs and TAMs and have reported corresponding results. This should be supported by summary tables compiling the relevant literature, including therapeutic approach, target cell population, key outcomes, and identified weaknesses. The currently provided Tables 1 and 2 are poorly informative and should be revised or expanded to better support this purpose. Additionally, when discussing survival analyses in correlation with CAFs and TAMs, it is essential to clearly specify the methods used for their evaluation and quantification.”

Response: We thank the reviewer for their close examination of our manuscript and recommendations. We have replaced Tables 1 and 2 with tables compiling therapeutic strategies targeting CAFs and TAMs. The tables include therapeutic approach, target cell population, key outcomes, identified weaknesses, and references.

Comment 2: “Moreover, in ovarian carcinoma, ascitic fluid is a very common phenomenon, especially in advanced stages, and it is important to highlight that investigating CAFs and TAMs in this context is of great value for understanding their role and potential impact on survival.”

Response: We appreciate the reviewer’s recommendation and have added a section with additional references to address this: “6.5. CAFs, TAMs, and ascitic fluid in epithelial ovarian cancer”.

Comment 3: “Separate paragraph on challenges and future goals might improve the impact of the review analysis.”

Response: Thank you for your suggestion. We added another section to address this: “6.6 Challenges and future goals”.

“Minor comments:”

Comment 4: “In the Introduction section, I suggest that at line 60, the description of the TME, including CAFs and TAMs, be presented in a more fluid and cohesive way. The current sections on CAFs (lines 70–78) and TAMs (lines 85–100) feel somewhat disjointed, as similar content is repeated within their respective sections. Consider reorganizing to avoid repetition and improve clarity. The Introduction should conclude clearly with the objective of the review.”

Response: We thank the reviewer for their observation and advice. We have re-written this portion of the introduction giving an overview of CAFs, TAMs, and the TME to minimize repetition and improve flow.

Comment 5: “Figure 2 fits more appropriately in Section 3.2 rather than 3.1. Please revise accordingly. I also suggest avoiding titles within the figures themselves, as all information should be provided in the figure legends. Similarly, any notes such as “created with BioRender” should appear only in the legend, not on the figure. Moreover, please correct all figures, as they appear distorted, and provide them in their original size with proper aspect ratios.”

Response: We apologize for this error. To avoid redundancy, we have combined the overview of CAFs and TAMs in the TME (Figure 1) and the CAF signaling pathways (Figure 2) into a single Figure: Figure 1. Titles and/or watermarks were removed from all figures, with “Created in biorender” stated only in the figure legends. Figures were replaced with undistorted, higher resolution versions.

Comment 6: “Please define all abbreviations accordingly (lines 136, 139, 191, 209, 210, 227, 228, 251, 245, 428, ...). Also explain all abbreviations under tables and images accordingly. 

Line 184: avoid bold

Ans: We have corrected it.

Lines 185-186: rather express as it would be interesting to investigate... instead of another analysis could examine...

Ans: Corrected

Lines 217-220: reference is missing

Ans: We have added the reference.

Line 240: ex-tracellular change to extracellular

Ans: corrected

Line 245: avoid capital first letters such us Ovarian Cancer”

Ans: Corrected

Response: We thank the reviewer for their close examination of our manuscript and for informing us of these errors. We have revised our abbreviation list, explained all abbreviations in tables and figures, and replaced the missing reference. In addition, we removed any unnecessary bold font, capitalization, and unintended dashes within words.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have carefully reviewed the authors’ responses to all comments and the corresponding revisions made to the manuscript. The authors have adequately and thoughtfully addressed each concern, including scientific accuracy, clarity, organization, and figure presentation. The revisions have significantly improved the quality, completeness, and readability of the manuscript.

I have no further comments or suggestions. In my opinion, the manuscript is now suitable for publication, and I recommend acceptance in its current form.

Author Response

Thank you very much for your decision. We sincerely appreciate your comments and suggestions, which have been fully addressed and have satisfied your prior recommendations.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have corrected the manuscript well overall; however, abbreviations remain an issue. Several abbreviations are either not explained at first mention or are reintroduced multiple times unnecessarily. Below are my minor comments:

Title: I suggest using the terminology cancer-associated fibroblasts and tumor-associated macrophages, rather than simply fibroblasts and macrophages.

Line 54: After “peritoneal metastasis,” I suggest adding: often resulting in the accumulation of peritoneal fluid (ascites) in ovarian carcinoma patients.

Lines 57–58: Please clarify whether the sentence referring to “current treatment” is extra and should be deleted.

Line 56: Use the “-“: poly-ADP-ribose…

Line 65: The abbreviation CAF is introduced here; it does not need to be redefined again (e.g., lines 110, 174, 211, and elsewhere).

Line 69: “CAFs are diverse” — please clarify: diverse cells or subtypes?

Line 97: Please remove the double space before “studies.”

Line 107: I would suggest shorter paragraph title, like avoiding the text after the “:”

Line 128: “Inflammatory CAFs (iCAFs)” — once the abbreviation is introduced, the full name does not need to be repeated. Please provide the full name for CXCL12 at first mention.

Line 132: apCAF: please clarify which CAF subtype this refers to.

Line 152: ECM has already been defined earlier; no need to redefine it here.

Line 159: Abbreviations used in this line are not explained.

Line 161: Please remove the double space before “While.”

Line 163: The tumor-suppressive role in early-stage ovarian cancer is mentioned; I suggest you explain how this role is supported.

Line 165: The mechanisms of bidirectional communication are only mentioned; please consider expanding this explanation.

Line 172: The paragraph title refers to CAF phenotypes, but the content mainly discusses autophagy; please revise for consistency.

Figure 1: Please explain all abbreviations of signaling pathways either in the figure legend or before first use in the text.

Line 174: CAF abbreviation is sufficient here; the full name is not needed.

Line 205–208: I suggest removing this sentence.

Line 221: Please use the abbreviation TME.

Line 231: Please revise the numbering; this section would by my oppinion fit better as subtitle 3.5.

Line 238: Please explain the abbreviation PI3K/AKT at first mention.

Line 242: Please explain the abbreviation EDA-NF.

Figure 2: Please add “Abbreviations:” before listing them; also, abbreviations should be introduced in the text, not only in the figure.

Line 251: Please explain FAP in the main text; explanation only in the figure legend is insufficient.

Lines 279 and 369: Please add a short introductory phrase (e.g., “Abbreviations:”) before listing or explaining abbreviations.

Line 299: The sentence on “M2 macrophages: … ” should be restructured into a more narrative, explanatory form rather than a listing style.

Line 359: I recommend to  change “Chapter 6” to 5.3 and adjust all corresponding subchapters accordingly.

Line 377: Please write out the full names of PD-1 and PD-L1 at first mention.

Line 430: Please explain BETi treatment in full name at first mention.

Line 462: I recommend to change numbering from 6.5 to 7.

Line 492: I recommend to change numbering from 6.6 to 8; the Conclusion would then become section 9.

Author Response

Response to comments from Reviewer 2: Round 2

The authors have corrected the manuscript well overall; however, abbreviations remain an issue. Several abbreviations are either not explained at first mention or are reintroduced multiple times unnecessarily. Below are my minor comments:

Comment 1: Title: I suggest using the terminology cancer-associated fibroblasts and tumor-associated macrophages, rather than simply fibroblasts and macrophages.

Response: We thank the reviewer for their recommendation. This alteration has been made to the title of the manuscript.

Comment 2: Line 54: After “peritoneal metastasis,” I suggest adding: often resulting in the accumulation of peritoneal fluid (ascites) in ovarian carcinoma patients.

Response: The suggested statement has been added.

Comment 3: Lines 57–58: Please clarify whether the sentence referring to “current treatment” is extra and should be deleted.

Response: Yes, that was a mistake and has been removed.

Comment 4: Line 56: Use the “-“: poly-ADP-ribose…

Response: The name has been adjusted as requested: “poly-ADP-ribose…”.

Comment 5: Line 65: The abbreviation CAF is introduced here; it does not need to be redefined again (e.g., lines 110, 174, 211, and elsewhere).

Response: Corrected.

Comment 6: Line 69: “CAFs are diverse” — please clarify: diverse cells or subtypes?

Response: …  CAFs are diverse: both functionally and transcriptionally. When CAFs undergo biological transitions, this will correlate to diverse subtypes.

Comment 7: Line 97: Please remove the double space before “studies.”

Response: The double space was removed.

Comment 8: Line 107: I would suggest shorter paragraph title, like avoiding the text after the “:”

Response: In the title of this section, all text after the colon has been removed.

Comment 9: Line 128: “Inflammatory CAFs (iCAFs)” — once the abbreviation is introduced, the full name does not need to be repeated. Please provide the full name for CXCL12 at first mention.

Response: “Inflammatory cancer-associated fibroblasts” was changed to “Inflammatory CAFs” and the full form, “C-X-C motif chemokine ligand 12 (CXCL12)”, was included.  

Comment 10: Line 132: apCAF: please clarify which CAF subtype this refers to.

Response: apCAFs refers to antigen-presenting CAFs, which highly express MHC class II molecules.

Comment 11: Line 152: ECM has already been defined earlier; no need to redefine it here.

Response: Corrected.

Comment 12: Line 159: Abbreviations used in this line are not explained.

Response: The full form for IL-10 was added. The full forms for TGF-β and IL-6 were listed earlier (section 3.1).  

Comment 13: Line 161: Please remove the double space before “While.”

Response: Corrected.  

Comment 14: Line 163: The tumor-suppressive role in early-stage ovarian cancer is mentioned; I suggest you explain how this role is supported.

Response: Transcriptomic analyses further suggest that early-stage tumors retain fibroblast programs associated with tissue homeostasis and favorable prognosis, whereas advanced ovarian cancers are enriched for inflammatory and myofibroblastic CAF signatures linked to immune suppression and poor outcome (Zhang M, Chen Z, Wang Y).

Comment 15: Line 165: The mechanisms of bidirectional communication are only mentioned; please consider expanding this explanation.

Response: We have added additional information regarding bidirectional communication to the text. “Bidirectional communication between tumor cells and cancer-associated fibroblasts (CAFs) is mediated through reciprocal signaling loops that evolve with disease stage and shape tumor progression, immune evasion, and therapy resistance. In high-grade serous ovarian carcinoma, tumor cells reprogram fibroblasts through TGF-β and inflammatory signaling, generating distinct CAF states that reciprocally promote tumor growth, ECM remodeling, and immune suppression via IL-6/STAT3 and CXCL12 signaling (Givel, Izar, Chai, Zhang)”.

Comment 16: Line 172: The paragraph title refers to CAF phenotypes, but the content mainly discusses autophagy; please revise for consistency.

Response: …  Autophagy-induced ovarian cancer cells promote activation and transformation of CAFs

Comment 17: Figure 1: Please explain all abbreviations of signaling pathways either in the figure legend or before first use in the text.

Response: All abbreviations have been listed.

Comment 18: Line 174: CAF abbreviation is sufficient here; the full name is not needed.

Response: Corrected.

Comment 19: Line 205–208: I suggest removing this sentence.

Response: This sentence was removed.

Comment 20: Line 221: Please use the abbreviation TME.

Response: Corrected.  

Comment 21: Line 231: Please revise the numbering; this section would by my oppinion fit better as subtitle 3.5.

Response: The “Potential therapeutic strategies targeting CAFs in epithelial ovarian cancer” section has been changed to 3.6 instead of 4. All subsequent section headings have been adjusted to correspond with the revised numbering.

Comment 22: Line 238: Please explain the abbreviation PI3K/AKT at first mention.

Response: Corrected.  

Comment 23: Line 242: Please explain the abbreviation EDA-FN.

Response: The full form of EDA-FN was listed in section 3.5, where a description has been added. EDA-FN is an alternatively spliced isoform of fibronectin that is selectively expressed in cancer-associated fibroblasts and tumor stroma, where it promotes extracellular matrix remodeling, tumor invasion, and immune evasion.

Comment 24: Figure 2: Please add “Abbreviations:” before listing them; also, abbreviations should be introduced in the text, not only in the figure.

Response: “Abbreviations:” was added to the legend of Figure 2, along with all other figures and tables. Key abbreviations have also been mentioned in the text.

Comment 25: Line 251: Please explain FAP in the main text; explanation only in the figure legend is insufficient.

Response: FAP is a cell surface serine protease highly expressed on cancer-associated fibroblasts that promotes tumor progression by remodeling the extracellular matrix and suppressing anti-tumor immune responses. A description has been added to section 3.5.

Comment 26: Lines 279 and 369: Please add a short introductory phrase (e.g., “Abbreviations:”) before listing or explaining abbreviations.

Response: Corrected.

Comment 27: Line 299: The sentence on “M2 macrophages: … ” should be restructured into a more narrative, explanatory form rather than a listing style.

Response: These sentences have been reworded into a more narrative/explanatory