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  • Qingshu Meng 1,†,
  • Liqun Huang 2,† and
  • Guosheng Yang 3,*
  • et al.

Reviewer 1: Saurabh Gupta Reviewer 2: Dirk Geerts

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The topic is relevant, and the literature coverage is extensive. Overall, the manuscript is promising but requires some revision before acceptance.  

  1. A major limitation is the absence of a unifying conceptual model explaining how EV-mediated metabolic reprogramming uniquely drives RCC progression.
  2. Address whether EV cargo changes are causal drivers or downstream consequences of metabolic reprogramming.
  3. Table 1 contains valuable information but is excessively long, heterogeneous, and difficult to navigate. Split Table 1 into subtables like Glycolysis-related EV cargos, Lipid metabolism-related EV cargos, Amino acid metabolism-related EV cargos.
  4. Discuss why metabolic–EV targeting strategies have not yet succeeded clinically, despite strong preclinical evidence.
  5. Several concepts-particularly the Warburg effect, HIF signaling, and miR-21-are repeatedly described across sections. Concise accordingly to improve clarity. 
  6. Minor grammatical and typographical errors are present throughout like subject verb agreement, pluralization of ‘EVs’). 

Author Response

The topic is relevant, and the literature coverage is extensive. Overall, the manuscript is promising but requires some revision before acceptance. 

Comments 1: A major limitation is the absence of a unifying conceptual model explaining how EV-mediated metabolic reprogramming uniquely drives RCC progression.

Response 1: Thank you for your suggestion. We agree with this comment. Therefore, we have added figure 1 and figure 2 to illustrate the conceptual models which show how do EV-mediated metabolic reprogramming drives tumor and RCC progression. We also updated the text in line 285-288, page 6, line 316-319, page7, line 431-434, page 11 and line 437-439, page 12 in the manuscript and highlighted the revised parts with yellow.

Comments 2: Address whether EV cargo changes are causal drivers or downstream consequences of metabolic reprogramming.

Response 2: Thank you for the comment. In cancer biology, the relationship between EV cargo alterations and metabolic reprogramming is not unidirectional but rather bidirectional and synergistic. Previous studies suggested that they operate within a positive feedback loop, making it difficult to classify EV cargo changes strictly as either causal drivers or downstream consequences. We updated the MS in part 4, page 7-8, line 324-329 and highlighted the modified part with yellow.   

 

Comments 3：Table 1 contains valuable information but is excessively long, heterogeneous, and difficult to navigate. Split Table 1 into subtables like Glycolysis-related EV cargos, Lipid metabolism-related EV cargos, Amino acid metabolism-related EV cargos.

Response 3: Thank you for the comment. We have, accordingly, split the table1 into table 1 to 3. Table 1 showed extracellular vesicles cargos and EVs mediated dissemination of the hypoxic signaling (page 9-10). Table 2 showed the lipid-laden cargo and enzymes in EVs and their roles in tumor progression (page 14). Table 3 showed the specific molecular cargos that EVs transport to reprogram amino acid metabolism in cancer. (page 17-18)

The text was also updated, and the modified parts can be found in line 344-345 and 350-351 for table 1, line 454-455, and 511-512 for table 2, line 520 and line 638-640 for table 3.

 

Comments 4：Discuss why metabolic–EV targeting strategies have not yet succeeded clinically, despite strong preclinical evidence.

Response 4: Thank you for the comment. Emerging preclinical studies identified that EVs are indispensable conductors of the complex metabolic orchestra within the tumor microenvironment and beyond. However, the gap between compelling preclinical data and clinical success in targeting the metabolism-EV axis in cancer is a classic example of the challenges in translating complex cancer biology into effective therapies. Despite strong mechanistic rationale, several interconnected biological, technical, and clinical hurdles still stand in the way. We discussed the key obstacles which remain in unveiling the EVs mediated mechanisms in cancer progression, as well as in translating these insights into effective therapeutic strategies. We also modified the MS and highlighted the revised part with yellow (page 16, line 610-615).

 

Comments 5：Several concepts-particularly the Warburg effect, HIF signaling, and miR-21-are repeatedly described across sections. Concise accordingly to improve clarity.

Response 5: Thank you for your suggestion. We carefully reviewed the MS and tried to remove the duplicate parts and make the content more concise and clearer. All revised parts were highlighted with yellow in the new version.

 

Comments 6：Minor grammatical and typographical errors are present throughout like subject verb agreement, pluralization of ‘EVs’).

Response 6: Thank you. We have checked all the text and revised the grammatical and typographical errors.

 

 

 

 

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In "Metabolic Messengers: Extracellular Vesicles as Central Mediators of Metabolic Reprogramming in Renal Cell Cancer", Meng and colleagues review the literature the role of EV's in kidney cancer. 

This is in general a well-written, well-referenced, and insightful study. The topic is timely and important. It is not yet suitable for publication:

  1. Major: the title states the review focuses on kidney cancer, and indeed especially the first 60% of the text does that. However, Table 1 mostly describes EV (cargo)'s in other cancers. The last part of the text then also described other cancers in detail. This is a bit confusing to me, and does not align with title and abstract. The authors should either explain their choices more clear, and adapt title and abstract, or indeed focus on kidney cancer alone.
  2. Without illustrations depicting the different signaling pathways this is very hard to read. In addition, the illustrations could be used to converge some of the routes described. 

Minor:

  1. Table 1 should have an extra column with: "protein, or circRNA, or miRNA" describing the nature of the content.
  2. The language on EV content targeting for new therapy is very limited, and warrants extension, since the authors claim in their abstract that EV's are important for novel therapy development.
  3. The abbreviation list should be in alphabetical order.
  4. Reference 153 is incomplete.

Author Response

In "Metabolic Messengers: Extracellular Vesicles as Central Mediators of Metabolic Reprogramming in Renal Cell Cancer", Meng and colleagues review the literature the role of EV's in kidney cancer.

This is in general a well-written, well-referenced, and insightful study. The topic is timely and important. It is not yet suitable for publication:

Comment 1: Major: the title states the review focuses on kidney cancer, and indeed especially the first 60% of the text does that. However, Table 1 mostly describes EV (cargo)'s in other cancers. The last part of the text then also described other cancers in detail. This is a bit confusing to me and does not align with title and abstract. The authors should either explain their choices more clear, and adapt title and abstract, or indeed focus on kidney cancer alone.

 

Response 1: Thank you for your comments. Accordingly, we tried to remove the content that is about the metabolic changes and therapies in other cancers in three parts including 2.1, 2.2, and 2.3 (ref 46, 57, 60, 61, 62, 105, 117, 135, 156, 161 in the primary MS were deleted) and only focused on renal cancers. On the other hand, recent discoveries have revealed some crucial mechanisms of tumorigenesis and potential therapeutic strategies, but no studies have yet investigated whether similar or different mechanisms exist in renal cell carcinoma. Therefore, for other parts, such as part 3 and part 4, especially 4.3 (Reprogramming Amino Acid Metabolism in Cancer by EVs), we included the recent relevant studies on this subject which are mainly on breast cancer, gastric cancer, lung cancer and CRC.

 

Comment 2:  Without illustrations depicting the different signaling pathways this is very hard to read. In addition, the illustrations could be used to converge some of the routes described.

Response 2: Thank you for your suggestion. We totally agree with this comment. Therefore, we added figure 1 and figure 2 to illustrate the conceptual models which show how do EV-mediated metabolic reprogramming drives tumor and RCC progression.

We also updated the text in line 285-288, page 6, line 316-319, page7, line 431-434, page 11 and line 437-439, page 12 in the revised manuscript and highlighted the revised parts with yellow.

Comment 3: Minor:

  1. Table 1 should have an extra column with: "protein, or circRNA, or miRNA" describing the nature of the content.

Response 3.1 Thank you. According to your suggestion, we added the type column in table 1 -3. The revised parts were highlighted with yellow.

  1. The language on EV content targeting for new therapy is very limited, and warrants extension, since the authors claim in their abstract that EV's are important for novel therapy development.

Response 3.2 Thank you for the comment. 

This review mainly summarizes the essential events in tumor-associated metabolic reprogram-m, explores how EVs released by metabolically deranged cells in cancer reprogram the renal cellular landscape, foster tumor initiation, proliferation, angiogenesis, immune evasion and therapy resistance, with particular focus on renal cancers. Understanding this EVs-mediated axis helps to unveil novel potential therapeutic targets for RCC patients. We also revised the summary in part 1 and highlighted the text with yellow (page 2, line 61-65).

Despite strong mechanistic rationale, several interconnected biological, technical, and clinical hurdles still stand in the way to clinical translations. We discussed the key obstacles which remain in unveiling the EVs mediated mechanisms in cancer progression, as well as in translating these insights into effective therapeutic strategies. We also modified the MS and highlighted the revised part with yellow (page 16, line 610-615) .

  1. The abbreviation list should be in alphabetical order.

Response 3.3 Thank you for the comment. We have revised the order of the abbreviation according to your comment in the revised MS.

  1. Reference 153 is incomplete.

Response 3.4 Thank you. Reference 153 in the last version is reference 143 in the new version. This is a newly on-line paper and the information is incomplete.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have sufficiently addressed my comments, the manuscript is now suitable for publication.