The Role of Metabolic Inflammation and Insulin Resistance in Obesity-Associated Carcinogenesis–A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In conclusion, this is an interesting review article that expands our knowledge on the connection between obesity-induced inflammation and insulin resistance to promote cancer development. However, a few concerns have been identified, which require responses from the authors to further improve the overall scientific quality of this review article. These concerns are listed below.

Concerns:

1. Expand on the role of specific chemokines/receptor signaling axis on obesity-induced-carcinogenesis.
2. Comment on the involvement of STAT5 in obesity-induced carcinogenesis because there is strong evidence that STAT5 activation by obesity-induced IL-6 expression supports tumor growth, survival, and metastasis.
3. Include information and discussion on the role/mechanisms of obesity-induced apoptosis via caspases in the extrinsic and intrinsic apoptosis.
4. You have a nice diagram in figure 1. However, it does not include signaling pathways. Therefore, provide another diagram showing obesity-induced release of IL-6 leading to IL-6/R activation and the various downstream signaling pathways that are activated and show their cross-talks.
5. There are papers, which have shown that intermittent fasting causes decline in obesity-induced breast cancer growth. Two of the references are provided below for your attention and inclusion.

• Son D.S. ,et al (2024) . Intermittent Fasting Attenuates Obesity-Induced Triple-Negative Breast Cancer Progression by Disrupting Cell Cycle, Epithelial-Mesenchymal Transition, Immune Contexture, and Proinflammatory Signature. Nutrients. 2024 Jul 01; 16(13)
• Xu Zhao et al. (2021) The role and mechanisms of intermittent fasting in tumors: friend or foe (Cancer Bio. Med. 18(10:63-73

There are new drugs that reduce HbA1c levels in obese individuals and are shown to significantly reduce obesity. An example is Ozempic (semaglutide). Is there any discussion or evidence that such obesity reduction drug decrease tumor growth and/or increase the risk of individuals for cancer

Author Response

Manuscript title: The Role of Metabolic Inflammation and Insulin Resistance in Obesity-Associated Carcinogenesis

We sincerely thank the reviewer for their thoughtful evaluation of our manuscript and for recognizing the importance of our review on the role of obesity-induced inflammation and insulin resistance in cancer development. We appreciate the constructive feedback and will address each concern point by point, detailing the clarifications and revisions made to improve the scientific quality of our article.

1) Expand on chemokine/receptor signaling axes in obesity-induced carcinogenesis

What the manuscript already contains. Figure 1 and Table 1 show inflammatory cells and mediators that promote proliferation, angiogenesis, EMT, and immune evasion, with explicit mention of pro-angiogenic chemokines from neutrophils and TAM-derived cytokines (TNF-α, IL-6, VEGF) driving NF-κB/STAT3/HIF-1α programs.

Proposed addition (Section “Tumor-Associated Inflammation,” end): lines 124-127
“Beyond cytokines, chemokine–receptor axes play a critical role in linking obesity-related inflammation to tumor progression. In particular, CCL2/CCR2 (monocyte/TAM recruitment), CCL5/CCR5 (immunosuppressive polarization, invasion), and CXCL12/CXCR4 (EMT, metastatic dissemination) activate NF-κB, JAK/STAT, and MAPK nodes to amplify angiogenesis, matrix remodeling, and immune evasion [32-34].”

Table 1 update. Add a row summarizing CCL2/CCR2; CCL5/CCR5; CXCL12/CXCR4 → NF-κB/JAK-STAT/MAPK → TAM influx, EMT, angiogenesis, cross-referencing the existing neutrophil/TAM entries.

2) Comment on STAT5 involvement (IL-6/obesity)

What the manuscript already contains. The JAK/STAT section currently emphasizes STAT3 activation by IL-6 and leptin, driving Cyclin D1, Bcl-XL, and VEGF (growth, survival, angiogenesis).

Proposed addition (same section, immediately after STAT3 paragraph): lines 100-114
“Although IL-6 most prominently activates STAT3, co-activation of STAT5 has been described in specific tumor contexts and may cooperate with STAT3 to sustain proliferation, survival, and metastatic behavior. We therefore note that IL-6/JAK signaling can engage STAT5, with downstream crosstalk to PI3K/Akt and NF-κB [21].

Obesity state creates a chronic inflammatory environment enriched in IL-6 derived from adipocytes, stromal cells, and myeloid populations. IL-6 interacts with the IL-6R/gp130 receptor complex, triggering JAK1/2 activation and phosphorylation of STAT3/STAT5, which dimerize and translocate to the nucleus [22-24]. Thereby, STAT3/5 drives transcriptional programs that favor tumor progression, including Cyclin D1 (cell-cycle entry), Bcl-XL (suppression of intrinsic/extrinsic caspase cascades), and VEGF (angiogenesis) [24].

Simultaneously, signaling adaptors such as SHP2 and Grb2 activate the MAPK/ERK pathway [25], while PI3K/Akt signaling amplifies survival and metabolism. Although SOCS3 typically detains JAK/STAT signaling, chronic IL-6 exposure in obesity reduces this control [26]. Although SOCS3 is induced as a classical brake on JAK/STAT signaling, persistent IL-6 exposure in obesity blunts this restraint. Furthermore, interactions with NF-κB and HIF-1α further amplify these signals, promoting EMT, angiogenesis, and metastasis [27]. Together, the IL-6/IL-6R/gp130 axis functions as a central integrator of metabolic inflammation and oncogenic signaling in obesity-associated carcinogenesis [23,24]. Figure 2.”

3) Include mechanisms of obesity-related apoptosis control via caspases (extrinsic/intrinsic):

What the manuscript already contains. Figure 1 and text already highlight inhibition of apoptosis through inflammatory signaling and STAT3-driven Bcl-XL expression.

Proposed addition (boxed sidebar within the “Molecular Pathways” section):
“Apoptosis pathways under metabolic inflammation.” lines 189-192
“Extrinsic signaling (Fas/TNF-R → caspase-8) and intrinsic mitochondrial pathways (cytochrome c → caspase-9) con-verge on executioner caspases-3/7. In obesity-inflammation, NF-κB/STAT3/PI3K-Akt upregulate anti-apoptotic proteins (e.g., Bcl-XL) and suppress caspase activation, fostering apoptosis resistance in the tumor microenvironment [33,34].”

4) Provide a diagram detailing IL-6 → IL-6R/gp130 signaling and downstream crosstalk:

What the manuscript already contains. Figure 1 summarizes the major pathways (NF-κB, JAK/STAT, PI3K/Akt/mTOR, HIF-1α) that obesity-related inflammation (e.g., IL-6) engages to promote proliferation, survival, angiogenesis, EMT, and immune evasion.

Proposed new Figure 2 (schematic & caption): Figure 2 line 356-366
Title: IL-6/IL-6R–gp130 axis in obesity-linked tumor promotion
Content: IL-6 binds IL-6R/gp130 → JAK1/2 → STAT3/STAT5 (targets: Cyclin D1, Bcl-XL, VEGF); branch signaling to PI3K/Akt and MAPK (via SHP2/Grb2); SOCS3 negative feedback; crosstalk with NF-κB and HIF-1α; outputs: proliferation, anti-apoptosis, EMT, angiogenesis.
Rationale link to existing Figure 1: This new figure “opens” the IL-6 arm already shown in the global network.

5) Add intermittent fasting (IF) and the two cited references:

What the manuscript already contains. The Diet and Nutrition section discusses diet patterns (e.g., Mediterranean diet) associated with lower cancer risk versus the Western diet.

Proposed addition (Diet and Nutrition, after Mediterranean diet paragraph): lines 279-293
“ Intermittent fasting (IF) has been associated with reductions in adiposity and systemic inflammation, improved insulin sensitivity, and metabolic reprogramming of the tumor microenvironment. Preclinical and translational re-ports—particularly in breast cancer—suggest attenuation of proliferation, EMT, and pro-inflammatory signaling under IF regimens [88]. IF has emerged as a promising approach in cancer research, particularly concerning its impact on obesity-induced triple-negative breast cancer (TNBC). A study by Son et al. (2024) provides substantial evidence that IF can significantly attenuate the progression of TNBC. The researchers found that IF disrupts the cell cycle and epithelial-mesenchymal transition (EMT), alters the immune contexture, and reduces pro-inflammatory signatures, all of which contribute to its cancer-fighting properties [88].

Similarly, Zhao et al. (2021) discuss the dual role of intermittent fasting in tumor dynamics. They highlight various mechanisms by which IF may act as both a protective and harmful influence on tumor development. This nuanced view suggests that while IF has potential benefits in slowing tumor progression and enhancing metabolic health, its effects can vary depending on the specific cancer context and individual metabolic state [89].

Together, these studies underscore the complex relationship between intermittent fasting, metabolic health, and cancer, particularly in the realm of TNBC, where IF may offer a therapeutic pathway to mitigate cancer progression and improve treatment outcomes [88,89].”

6) Address GLP-1 receptor agonists (e.g., semaglutide/Ozempic) and cancer outcomes: lines 319-324.

What the manuscript already contains. The Metabolic Modulation Therapies section already covers GLP-1 receptor agonists (GLP-1RAs), noting weight reduction, restoration of insulin sensitivity, and signals suggesting inhibition of tumor progression via dampening inflammatory cytokines and metabolic normalization (with caveats about adverse effects). and supporting references in your bibliography.

Proposed addition (end of that subsection):
“Regarding semaglutide, mechanistic plausibility exists—via weight loss, improved insulinemia/insulin sensitivity, and reduced inflammatory tone—that GLP-1RAs could reduce pro-tumorigenic signaling in obesity. However, clinical evidence on tumor growth reduction or cancer risk modulation remains limited and mixed, and long-term oncologic outcomes are still under active investigation. We therefore maintain a balanced stance: GLP-1RAs are valuable metabolic tools with potential anticancer benefits mediated indirectly through metabolic and inflammatory improvements, but definitive cancer endpoints will require prospective data.”

The authors express recognition for the reviewer's feedback, highlighting how it has improved the clarity and scientific integrity of their review. They believe their revisions address the concerns raised and enhance the work's significance regarding obesity-related inflammation, insulin resistance, and cancer progression. They hope the revised manuscript meets publication standards.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript, entitled "The role of metabolic inflammation and insulin resistance in obesity associated carcinogenesis," is a review of the mentioned field.
The manuscript provides an interesting, summarized overview of several interplaying mechanisms linking inflammation, obesity, and cancer. 
However, the authors failed to mention the aim or objective explicitly, nor did they provide a bibliographic search strategy or flow chart. 
They mention this in the last paragraph of the abstract, stating that "this review explores the mechanistic interplay between obesity induced inflammation, insulin resistance, and cancer progression, discusses the molecular pathways involved, and highlights emerging therapeutic approaches targeting these intersecting tumor promotion axes."
This imprecise approach impairs the reader's ability to identify how deeply the bibliographic search was conducted or how the authors decided to include the cited papers.
Clearly, this manuscript is of interest to this journal and belongs to the category of Scoping Review. Consequently, it should be restructured by following the suggested structure in the "Instructions for authors" of this journal under the study design as a Scoping Review.

Author Response

We sincerely thank the reviewer for their careful reading of our manuscript and for recognizing its relevance and value in exploring the links between obesity, inflammation, insulin resistance, and cancer development. We appreciate the constructive points raised and would like to clarify our approach while highlighting the revisions made to strengthen the manuscript.

1. Aim and Objective
   We agree that explicitly stating the aim improves clarity. In response, we have revised the abstract and introduction to include a clear objective: “This review explores the mechanistic interplay between obesity-induced inflammation, insulin resistance, and cancer progression, with emphasis on molecular signaling pathways and emerging therapeutic strategies.” This makes the purpose of our work explicit from the outset.
2. Bibliographic Search Strategy and Flowchart
   While we acknowledge the importance of transparency in literature selection, our intention was not to perform a formal systematic or scoping review, but rather to provide a narrative and mechanistic synthesis of key experimental, translational, and clinical studies. This format is consistent with traditional review articles commonly published in this journal. We respectfully disagree that a PRISMA-style flowchart or scoping review structure is essential, as our manuscript does not aim to comprehensively map the entire literature but rather to integrate and interpret mechanistic insights across interconnected pathways.
3. Reviewer 1’s Concerns Already Addressed
   We have incorporated additional mechanistic depth (chemokine–receptor axes, STAT5, apoptosis control via caspases, intermittent fasting, GLP-1 receptor agonists) and added Figure 2 (IL-6/IL-6R/gp130 signaling). These revisions align with the constructive feedback from Reviewer 1 and improve scientific quality without requiring a full restructuring into a scoping review format.
4. Journal Category Clarification
   The reviewer suggested reclassification as a Scoping Review. We respectfully submit that the scope and intent of our manuscript fit more closely within the Narrative/Mechanistic Review category, which allows integration and interpretation of complex biological processes rather than exhaustive mapping of citations. This approach aligns with the journal’s acceptance of both traditional reviews and scoping/systematic formats, depending on the authors’ aims.

We greatly appreciate the reviewer’s suggestions, which prompted us to strengthen the aim statement, clarify our literature search approach, and refine the manuscript’s scientific contribution. While we acknowledge the merits of a scoping review format, we believe that our narrative, mechanistic approach is more appropriate for the intended readership and aligns with the tradition of conceptual reviews in this field. We hope that our clarifications and revisions address the concerns raised and that the revised manuscript now meets the journal’s standards.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I commend the authors for satisfactorily addressing all the concerns raised by the reviewer of the original version of their review manuscript. In addition, I commend them for the revisions and incorporating additional references to the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors answered the reviewers' comments and questions.
However, they expressed their desire to maintain a narrative review format and emphasized that they did not want a scoping or systematic review.
As a narrative review, it is expected that the authors clarify how they decided to include the bibliography examined in this manuscript, at least by indicating their management of the keywords or combinations.
Furthermore, it is not a section under the subheading or concept of limitations of this study, as the authors did for other works cited in this narrative review. 
Both characteristics, being respectively the rights of the authors, introduce the concept that maybe they wanted more to go into the field of science difusión.