PONE-D-24-48029The potential role of cuproptosis-related genes for therapy and immunoregulation in pan-cancerPLOS ONE

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Additional Editor Comments:

Please address the comments from reviewer 1. With regard to reviewer 2, please address the reviewer's concern about novelty.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1:  This study explored the expression pattern and clinical role of cuproptosis-related genes in 34 different cancers. The results displayed that the expressions of cuproptosis-related genes were significantly different in various cancer types. Authors found that the higher the level of cuproptosis-related genes expressed, the higher the survival in patients suffering from KIRC, and KIPAN. Interestingly, the expression of some cuproptosis-related genes was negatively associated with immune-related scores, while SLC31A1 had a positive association with StromalScore, ImmuneScore, and EstimateScore in LAML. It is possible that cuproptosis-related genes have prognostic value for different cancers. The study is interesting and substantial. There are only few minor issues to address.

1. All abbreviations in the Abstract should be deciphered.

2. Introduction should mention existing controversies about cuproptosis role in cancers and tumour microenvironment; explore recent reviews which questioned the role of cuproptosis in cancer microenvironment. The current study is focused on the immune network, therefore, authors should extend the Introduction/Discussion and mention the controversial role of cuproptosis in the cancer microenvironment (see this review by Zhao et al., 2024 https://pubmed.ncbi.nlm.nih.gov/39068453/)

3. Fig 2 quality is low in the provided pdf file. It is impossible to read letters. Authors should provide a better-quality figure and increase the font. However, the quality of the original file is ok. I have downloaded the file, and it is possible to read letters there. Authors should make sure that the printed version is readable.

4. There are some English mistakes. It is necessary to confirm what is “drug sensibility”? I guess, authors meant to write “drug sensitivity” or “ drug susceptibility”. They need to correct this all over the text.

5. Line 343: authors should correct this phrase ‘ subsequent treatment with the mechanism of cuproptosis.” – It should be “ subsequent treatment with drugs which activate cuproptosis”. ( or similar in the meaning).

6. Discussion needs a lot of English editing. There are lots of phrases which should be corrected/re-written ( line 349 etc)

7. Discussion should be extended. For instance, authors should indicate how FDX1 can be targeted and how it is involved into the regulation of immune responses in TME etc.

8. Authors need to focus on the most promising genes. Current discussion is too general, vacuous. It is unclear which genes should be recommended and used for calculation of predictive scores.

Reviewer #2:  The study provides a compelling exploration of the emerging mechanism of cuproptosis, emphasizing its significance as a promising approach in cancer research. By systematically analyzing the expression patterns and clinical relevance of cuproptosis-related genes across various cancer types, the study highlights the potential of this mechanism as a novel therapeutic avenue. The integration of tumor mutation burden, immune-related scores, tumor microenvironment dynamics, and drug sensitivity evaluations contributes to a better understanding of how these genes may influence cancer progression and prognosis. Overall, the study presents a coherent methodological flow and offers valuable insights within the broader context of cancer research.

However, the manuscript faces two critical issues:

1-A more comprehensive set of cuproptosis-related genes, including solute carrier family 31 member 1 (SLC31A1), dihydrolipoamide S-acetyltransferase (DLAT), ATPase copper transporting beta (ATP7B), dihydrolipoamide dehydrogenase (DLD), dihydrolipoamide branched chain transacylase E2 (DBT), dihydrolipoamide S-succinyltransferase (DLST), glycine cleavage system protein H (GCSH), lipoic acid synthetase (LIAS), ferredoxin 1 (FDX1), lipoyltransferase 1 (LIPT1), pyruvate dehydrogenase E1 subunit beta (PDHB), and pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), has already been extensively studied in the literature. These genes were analyzed for their prognostic roles, immune correlation, tumor microenvironment interaction, treatment sensitivity, and therapeutic response across various cancers, with experimental validation also performed specifically for prostate cancer.

The genes analyzed in the referenced study encompass those included in this manuscript and also incorporate additional genes. This overlap significantly diminishes the novelty of the present work.

Reference:

Yang, L., Tang, Y., Zhang, Y. et al. Comprehensiveness cuproptosis related genes study for prognosis and medication sensitiveness across cancers, and validation in prostate cancer. Sci Rep 14, 9570 (2024). https://doi.org/10.1038/s41598-024-57303-8

2- While pan-cancer studies are valuable for analyzing the broad effects of genes across multiple cancer types, these studies often rely on data from various computational tools, web-based platforms, and databases. Drawing impactful conclusions that guide future research requires validation in specific cancer types. For journals with a high quartile ranking, such as PLOS ONE, validation of findings in one or more cancer types is particularly essential. The absence of experimental validation in the current manuscript limits its impact and reduces its suitability for publication in a journal of this caliber.

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Reviewer #1: Yes:  Olga A. Sukocheva, PhD MPH

Reviewer #2: No

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The potential role of cuproptosis-related genes for therapy and immunoregulation in pan-cancer

PONE-D-24-48029R1

Dear Dr. Li,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Hilary A. Coller

Academic Editor

PLOS ONE