Metabolic Reprogramming as a Therapeutic Target in Cancer: A Qualitative Systematic Review (QualSR) of Natural Compounds Modulating Glucose and Glutamine Pathways

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review entitled “Cancer Therapeutics Innovation: Metabolic Perspective in Tumor Growth, Treatment, Management and Prevention -Qualitative Systematic Review (QualSR)” by Dr. Enwere et al., describes the effect of metabolic modulation on cancer management  as well as it mentioned the effect of some natural compounds that might affect these metabolic functions especially for cancer treatment. The review has several positive points such as it underscores the metabolic approach as one of the personalized approaches to fight against cancer as well as it integrated some natural compounds with conventional therapies for better targeting tumors. However, several points require clarification or modification such as:

 

1- Title: treatment, management and prevention all can be summed up by tumor management. Moreover, the title did not mention anything related to the proposed natural compounds that the review discussed. Therefore, the authors are encouraged to modulate the title to a better representative one.

 

2-Hypothesis: the metabolic variations of cancer cells are well documented before as well as the role of the mentioned natural compounds. It is good to make more evidences for their effect and the positive role of adopting this metabolic approach as adjunctive therapy for cancer or as one of the personalized medicine arms. Therefore, in line 28, the authors mentioned “synthesizes evidence” is not appropriate may be provide or offer will be better used. In another part, line 830, the authors mentioned that their results are in agreement with others and they provide references which contradict the word synthesize evidence.

-Moreover, the author mentioned in section “6.4. Final Thoughts” that “The shift from a gene-centric to a metabolism-focused cancer treatment model holds great promise for the future of oncology.” I think this statement is not fully correct taking in account the limitations and the drawbacks of natural compounds mentioned by the authors and the difficulty to provide a promising remedy with the mentioned compounds, we cannot replace the genetic personalized medicine to metabolic approach, and instead it can help as one of the important arms in personalized medicine.

- After all the mentioned limitations, side effects and problems with pharmacokinetic of the proposed natural products, how we can consider the metabolic approach as a promising approach for cancer treatments? The authors are encouraged to provide some solutions and successful clinical trials for these compounds.

 

3- Results:

-The results can be separated as sections with numbers.

-The results and discussion section can be combined as several statements were repeated in both sections that make redundancy.

-In result section there was no information about the effect on mitochondria or the metabolic effects, however, all results were focused on the natural products selected.

-It is better to summarize all results in tables and mentioning the effect of each natural compound, side effects, drawbacks, and limitations.

 

Discussion

-Several sections can be combined as they are targeting the same point such as 4.4. Metabolic Modulation and Immunotherapy should contain the other 2 titles : (4.10. Metastasis and the Role of the Microenvironment and 4.11. Metabolic Reprogramming and Tumor Microenvironment), to prevent repeating several statements.

-The author did not provide any information of the effect of the proposed natural products on the metastasis and the tumor microenvironment sections 4.10, and 4.11.

-The authors did not mention some important immunosuppressive cells in TME and their role with metabolic dysfunction such as Treg (suppressor T cells) and myeloid-derived suppressor cells (MDSCs).

 

-The authors did not mention anything related to epithelial to mesenchymal transition in metastasis section. Please check this manuscript: Schwager et al., 2022. Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity. iScience. 2022 Oct 1;25(10):105190.

 

 

Minor points:

-Acronyms should be stated first then the acronym will be used such as:

 1-BBR (in line 450, 452, 454, 456 and 463) is it berberine?

2- PRISMA  guide lines was mentioned in line 110, and Systematic Reviews and Meta-Analyses (PRISMA) guidelines in line 228.

Author Response

Reviewer 1, Comment 1:
“Title: treatment, management and prevention all can be summed up by tumor management. Moreover, the title did not mention anything related to the proposed natural compounds that the review discussed. Therefore, the authors are encouraged to modulate the title to a better representative one.”

 

Our Response: We thank the reviewer for this valuable feedback regarding title clarity and comprehensiveness. We agree that the original title contained redundant terminology and failed to adequately highlight the natural compounds focus of our review. We have revised the title to: '1' This revision eliminates redundancy while clearly identifying both the metabolic focus and the natural compounds emphasis that characterizes our systematic review, providing readers with a more accurate representation of the manuscript's scope and contributions.

 

Changes Made: The title has been revised to: 'Metabolic Reprogramming as a Therapeutic Target in Cancer: Natural Compounds Modulating Glucose and Glutamine Pathways - A Qualitative Systematic Review (QualSR ) (Page 1, Line 2).

 

Reviewer 1, Comment 2:
“Hypothesis… the metabolic variations of cancer cells are well documented… line 28, ‘synthesizes evidence’ is not appropriate… ‘Final Thoughts’ statement about replacing genetic with metabolic model not correct… After limitations, how can we consider metabolic approach promising? Authors should provide solutions and successful clinical trials.”

 

Our Response: We appreciate this critical feedback. We have replaced “synthesizes evidence” with “offers a comprehensive synthesis” to avoid contradiction. We have reframed the “Final Thoughts” section to emphasize metabolic approaches as a complementary strategy within personalized oncology, not a replacement of genetic medicine. Additionally, we expanded the Conclusion to include recent successful clinical trials (e.g., high-dose vitamin C in rectal cancer, curcumin with gemcitabine in cholangiocarcinoma, and berberine in hepatocellular carcinoma).

Changes Made:

• Page 2, Line 28: replaced “synthesizes evidence” with “offers a comprehensive synthesis.”
• Page 60, Lines 1230–1240: revised “Final Thoughts” to emphasize complementarity.
• Page 58–61: added section on successful clinical trials and translational strategies.

 

Reviewer 1, Comment 2:
“After all the mentioned limitations, side effects and problems with pharmacokinetics of the proposed natural products, how can we consider the metabolic approach as a promising approach for cancer treatments? The authors are encouraged to provide some solutions and successful clinical trials for these compounds.”

Our Response:
We thank the reviewer for this insightful comment. We agree that pharmacokinetic barriers and side effects represent critical challenges in translating natural metabolic modulators into clinical practice. To address this, we have added a section in the Result and Discussion section highlighting practical solutions (e.g., nanoparticle formulations, structural analogues, and biomarker-driven patient stratification) and referenced successful clinical trials that demonstrate the feasibility of these interventions. These additions strengthen the manuscript by providing translational relevance and evidence-based optimism regarding the metabolic approach.

Changes Made:

• Page 17, Lines 498 - 514: New text added discussing nanotechnology-based delivery systems, combination regimens, and biomarker-guided use as solutions to pharmacokinetic barriers.
• Page 13–14: Expanded Conclusion to highlight evidence from successful clinical trials, including:
• Intravenous high-dose vitamin C in rectal cancer 44.4% pathologic complete response with chemoradiotherapy.
• Curcumin combined with gemcitabine enhanced efficacy in resistant cholangiocarcinoma.
• Berberine demonstrating enrichment and tumor-suppressive activity in hepatocellular carcinoma and lung adenocarcinoma.

 

Reviewer 1, Comment 3:

3- Results:

-The results can be separated as sections with numbers.

-The results and discussion section can be combined as several statements were repeated in both sections that make redundancy.

-In result section there was no information about the effect on mitochondria or the metabolic effects, however, all results were focused on the natural products selected.

-It is better to summarize all results in tables and mentioning the effect of each natural compound, side effects, drawbacks, and limitations.

 

Our Response: We thank the reviewer for these organizational recommendations. We have:

• Divided Results into numbered subsections.
• To reduce the overlapping statements between Results and Discussion, both sections have been merged.
• Added explicit mitochondrial findings (e.g., curcumin’s impact on mitochondrial dysfunction, resveratrol’s suppression of HIF-1α).
• Included Table 3 summarizing natural compounds, their mechanisms, side effects, and limitations.

Changes Made:

• Lines 388–495: Results reorganized into numbered subsections.
• Page 12: New Table 3 added. (Table 3. Natural compounds in metabolic modulation: mechanisms, effects, limitations, and clinical relevance).
• Page 12, Lines 388–495: new sentences on mitochondrial impacts.

 

Reviewer 1, Comment 4:

 

4 Discussion

-Several sections can be combined as they are targeting the same point such as 4.4. Metabolic Modulation and Immunotherapy should contain the other 2 titles : (4.10. Metastasis and the Role of the Microenvironment and 4.11. Metabolic Reprogramming and Tumor Microenvironment), to prevent repeating several statements.

-The author did not provide any information of the effect of the proposed natural products on the metastasis and the tumor microenvironment sections 4.10, and 4.11.

-The authors did not mention some important immunosuppressive cells in TME and their role with metabolic dysfunction such as Treg (suppressor T cells) and myeloid-derived suppressor cells (MDSCs).

 

-The authors did not mention anything related to epithelial to mesenchymal transition in metastasis section. Please check this manuscript: Schwager et al., 2022. Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity. iScience. 2022 Oct 1;25(10):105190.

 

Reviewer 1, Comment 4:
“Discussion: merge overlapping sections (4.4, 4.10, 4.11)… add info on natural products’ effects on metastasis and TME… mention Tregs, MDSCs… include EMT in metastasis section with Schwager et al. 2022 citation.”

 

The authors did not mention anything related to epithelial to mesenchymal transition in metastasis section. Please check this manuscript: Schwager et al., 2022. Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity. iScience. 2022 Oct 1;25(10):105190.

Our Response: We thank the reviewer for these insightful suggestions. To address redundancy, we merged Sections 4.4, 4.10, and 4.11 under “Metabolic Modulation, Tumor Microenvironment, and Metastasis.” We incorporated evidence on natural compounds’ effects on TME and metastasis, expanded the immunology content to include Tregs and MDSCs, and added EMT mechanisms with the cited Schwager et al. (2022) reference.

We have addressed comprehensively the role of metabolic reprogramming is a critical enabler of metastasis, directly fueling the Epithelial-to-Mesenchymal Transition (EMT), in the revised manuscript. Specifically, we have expanded the discussion on EMT's role in metastasis, particularly in relation to glucose metabolic heterogeneity, and incorporated the suggested reference (Schwager et al., 2022).

Changes Made:

• Page 12, Lines 388 –552: merged sections into a unified subsection.
• Page 12, Lines 496 –502: added discussion on Tregs and MDSCs.
• Page 12, Lines 512– 514: included EMT mechanisms and citation of Schwager et al., iScience, 2022.

 

 

Reviewer 1, Comment 5 (Minor):
1. Acronyms should be stated first… BBR for berberine,

2. 2- PRISMA guidelines was mentioned in line 110, and Systematic Reviews and Meta-Analyses (PRISMA) guidelines in line 228.

 

Our Response: We thank the reviewer for noting these inconsistencies. We corrected acronym usage throughout the manuscript, ensuring each term is spelled out at first mention (e.g., Berberine [BBR], Epigallocatechin gallate [EGCG]).

We thank the reviewer for this important observation regarding the PRISMA guidelines citation. We acknowledge the inconsistency in our manuscript where PRISMA guidelines are mentioned in both line 110 and line 228.

To address this concern, we have:

 

Standardized the terminology throughout the manuscript to consistently use "PRISMA 2020 guidelines" as this is the most current version

Changes Made:

• Page 5, Line 188 onwards: corrected EGCG usage.
• Page 10, Lines 411 onwards: corrected BBR usage
• Page 6, Line 230: PRISMA 2020 guidelines

 

Reviewer 2 Report

Comments and Suggestions for Authors

Summary

The authors present a qualitative systematic review (QualSR) on how natural compounds that target the availability of glucose and glutamine to tumor cells can assist or augment standard cancer therapies. Biomarker-driven patient stratification will optimize clinical translation and therapeutic impact in treatment-resistant cancers.  The authors also provide a synthesis of preclinical and clinical evidence on metabolic-targeted therapies while emphasizing mechanisms of action, therapeutic efficacy, and clinical publications of natural compounds. There are several issues that the authors must address to enhance the accuracy and utility of the information reviewed.

 

Major comments

1. A major focus of the author’s review describes how metabolically targeted therapies using natural compounds, particularly those modulating glucose and glutamine metabolism, can improve cancer treatment outcomes.

Comment: While the author’s focus is important, many of the topics presented in their review were also described in two recent papers (https://doi.org/10.1007/s10863-025-10059-w; https://doi.org/10.1186/s12916-024-03775-4). The information in these papers can complement and strengthen the conclusions of the author’s review.

 

2. On lines 195-6, the authors state; “cancer cells' remarkable adaptability, requires careful consideration of treatment timing, dosing, and combination strategies.

Comment:  Is the adaptability of cancer cells to metabolic stress better than that of normal cells? Most cancer cells contain many mutations that would reduce adaptability. As the authors emphasize, most cancer cells will die or growth arrest without the availability of glucose and glutamine.   Consequently, the remarkable adaptability of cancer cells depends largely on the abundance of glucose and glutamine in the microenvironment. Normal cells are more metabolically flexible than cancer cells and can metabolize a broader range of fuels thus representing greater adaptability than cancer cells.

 

3. The authors state on lines 92-94 that; “The interdependence of glucose and glutamine metabolism presents an opportunity to simultaneously target these pathways, disrupting cancer cell energy supply and proliferation”.

Comment:  Is it better to target the glycolysis and glutaminolysis pathways or to simply restrict availability of glucose and glutamine?  This is important as the glycolysis and glutaminolysis pathways are also expressed in normal cells and their targeting might negatively impact normal cell function.

 

4. In section 4.11, Metabolic Reprogramming and Tumor Microenvironment, the authors state, “The Warburg Effect, characterized by cancer cells' preference for anaerobic glycolysis even in oxygen-rich environments, is not merely a metabolic anomaly but a sophisticated survival adaptation”.

Comment: The information presented in this section is confused with teleology.  Cancer cells are not designed with a preference for anaerobic glycolysis but become dependent on cytoplasmic substrate level phosphorylation (glycolysis) for energy due to insufficiency of oxidative phosphorylation.  Consequently, it is mitochondrial dysfunction causing a HIF-1a-linked upregulation of glycolysis that becomes a necessity for cancer cell survival.  This explanation provides a mechanistic explanation to the phenomenon rather than preference.

Minor comment

1. On line 873-4, the authors mention Seyfried’s “Press-Pulse” approach but no reference to this approach is presented.

Author Response

Reviewer’s Comment:

Comment 1

“A major focus of the author’s review describes how metabolically targeted therapies using natural compounds, particularly those modulating glucose and glutamine metabolism, can improve cancer treatment outcomes. While the author’s focus is important, many of the topics presented in their review were also described in two recent papers (https://doi.org/10.1007/s10863-025-10059-w; https://doi.org/10.1186/s12916-024-03775-4). The information in these papers can complement and strengthen the conclusions of the author’s review.”

 

Our Response:

We thank the reviewer for this valuable suggestion. We have carefully reviewed the recommended references and integrated their insights into both the Introduction and Discussion sections of the revised manuscript. Specifically, these papers provided additional evidence supporting the role of metabolic reprogramming in cancer progression and highlighted the translational challenges and opportunities of targeting glucose and glutamine pathways. Their inclusion strengthens our review by positioning our findings within the most recent scientific discourse and providing a broader context for the conclusions drawn.

 

Changes Made:

 

Introduction (Page 4, Lines ~163–165): Added a paragraph acknowledging and citing the first recommended studies to frame our review within current literature.

 

Discussion (Page 12, Lines 536–539): Incorporated the complementary evidence from the paper when discussing translational implications and clinical trial directions.

 

Updated Reference List to include both cited works.

 

Reviewer’s Comment (Lines 195–196):

Comment 2.
On lines 195–6, the authors state: ‘cancer cells' remarkable adaptability, requires careful consideration of treatment timing, dosing, and combination strategies.’ Comment: Is the adaptability of cancer cells to metabolic stress better than that of normal cells? Most cancer cells contain many mutations that would reduce adaptability. As the authors emphasize, most cancer cells will die or growth arrest without the availability of glucose and glutamine. Consequently, the remarkable adaptability of cancer cells depends largely on the abundance of glucose and glutamine in the microenvironment. Normal cells are more metabolically flexible than cancer cells and can metabolize a broader range of fuels thus representing greater adaptability than cancer cells.

Our Response:
We thank the reviewer for this important clarification. We agree that normal cells possess greater inherent metabolic flexibility than cancer cells. Our original wording was imprecise and may have suggested otherwise. What we intended to emphasize is that cancer cells exhibit conditional adaptability within the tumor microenvironment when glucose and glutamine are abundant, enabling them to sustain growth despite oncogenic mutations. This adaptability is not absolute but context-dependent, contrasting with the broader metabolic flexibility of normal cells. We have revised the text to clarify this distinction.

Changes Made:

• Methods/Rationale Section (Page 5, Lines 197–202): Revised sentence now reads:

“While cancer cells are less metabolically flexible than normal cells due to accumulated mutations, they display a conditional adaptability within the tumor microenvironment—particularly when glucose and glutamine are abundant. This context-dependent adaptability underscores the importance of carefully considering treatment timing, dosing, and combination strategies when targeting cancer metabolism.”

 

Reviewer Comment

Comment 3:

Lines 92–94: “The interdependence of glucose and glutamine metabolism presents an opportunity to simultaneously target these pathways, disrupting cancer cell energy supply and proliferation.”
Comment: Is it better to target the glycolysis and glutaminolysis pathways or to simply restrict availability of glucose and glutamine? This is important as the glycolysis and glutaminolysis pathways are also expressed in normal cells and their targeting might negatively impact normal cell function.

 

Our Response

We thank the reviewer for this important translational question. We agree that global deprivation of glucose or glutamine is neither practical nor desirable, given essential requirements for normal tissues and the risks of hypoglycemia, sarcopenia/cachexia, and immune suppression. Our intended emphasis is selective metabolic modulation, not blanket substrate restriction. Tumors frequently overexpress transporters/enzymes (e.g., GLUT1, HK2, PFKFB3, LDH-A; SLC1A5, GLS1) and display heightened dependency on glycolysis and glutaminolysis relative to most normal tissues. This differential dependency, combined with dosing/scheduling, biomarker-guided patient selection (e.g., GLUT1/SLC1A5 expression, FDG-PET avidity), and targeted delivery (e.g., nanoformulations, prodrugs), creates a therapeutic window to modulate these pathways in tumors while limiting impact on normal cells. We have revised the Introduction to clarify this distinction and added a Discussion paragraph outlining clinical guardrails and solution strategies.

 

Changes Made

1) Introduction — precise sentence replacement

Location: Page 2-3, Lines 92–98 (single sentence).
Delete:

“The interdependence of glucose and glutamine metabolism presents an opportunity to simultaneously target these pathways, disrupting cancer cell energy supply and proliferation.”

Insert (new sentence):

“Because many tumors overexpress glucose and glutamine transporters/enzymes (e.g., GLUT1, HK2, PFKFB3, LDH-A; SLC1A5, GLS1) and exhibit heightened reliance on these fuels, the interdependence of glycolysis and glutaminolysis creates a therapeutic window to selectively modulate—rather than globally suppress—these pathways (e.g., with GLS1, LDH-A, or GLUT1 inhibitors, transporter-directed delivery, and biomarker-guided dosing), thereby impairing tumor bioenergetics while preserving normal tissue function.”

 

Reviewer Comment

Comment 4:

 

1. In section 4.11, Metabolic Reprogramming and Tumor Microenvironment, the authors state, “The Warburg Effect, characterized by cancer cells' preference for anaerobic glycolysis even in oxygen-rich environments, is not merely a metabolic anomaly but a sophisticated survival adaptation”.

Comment: The information presented in this section is confused with teleology.  Cancer cells are not designed with a preference for anaerobic glycolysis but become dependent on cytoplasmic substrate level phosphorylation (glycolysis) for energy due to insufficiency of oxidative phosphorylation.  Consequently, it is mitochondrial dysfunction causing a HIF-1a-linked upregulation of glycolysis that becomes a necessity for cancer cell survival.  This explanation provides a mechanistic explanation to the phenomenon rather than preference.

 

Our Response

We thank the reviewer for this critical clarification. We agree that our initial wording inadvertently implied teleology. Cancer cells do not “prefer” glycolysis; rather, they often develop mitochondrial insufficiency (due to oncogenic mutations, hypoxia, or mitochondrial dysfunction), which drives HIF-1α stabilization and upregulation of glycolytic genes. This reprogramming enforces reliance on cytoplasmic substrate-level phosphorylation as a survival necessity, not an evolutionary preference. We have revised Section 4.11 to remove teleological language and to emphasize the mechanistic basis of the Warburg Effect.

Changes Made

Page 13, Line 514 -550: The entire section was reworded currently it does not suffer from the same teleological confusion flagged earlier.

 

Reviewer Comment

Minor comment

1. On line 873-4, the authors mention Seyfried’s “Press-Pulse” approach but no reference to this approach is presented.

 

Our Response

We thank the reviewer for this important observation. This has been addressed.

 

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors addressed most of my comments, and the review greatly improved. I recommend it for publication.