Metabolic Reprogramming of B Cells in Cancer: Effects of Altered Energetics

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

Sarkar et al have written an extensive, comprehensive review, discussing how metabolic reprogramming of B cells can be taken advantage of for future cancer treatments. However, the manuscript has a solid structure and material, some major and minor comments should be addressed before the manuscript can be accepted

 

 

Major

• authors should emphasise a clear distinction between malignant B cells and tumor-infiltrating B cells and those two malignancies should be addressed in separate sections ( B cell lymphomas/leukemias)
• The therapeutic section should be followed by an extensive section on the safety measures and toxicity discussions. Authors should provide a table of scturcuraise current clinical trials (NCT numbers/trial phase specifics/enrollment numbers/efficacy/safety data/completed and ongoing trials
• Authors should include a section describing how the review was performed, how many studies supporting /not supporting stated claims
• authors have to be clearer in discussing murine and human data to highlight similarities and differences in murine vs human biology

 

 

 

Minor

please in the graphical abstract, select different backgounr; the light green is difficult to read

Author Response

We sincerely thank the editor and all the reviewers for their careful reading of our manuscript and for their constructive and insightful comments. The authors greatly appreciate the suggestions, which have helped us improve the clarity, structure, rigor, and overall impact of the review. We have revised the manuscript extensively in response to these comments. Below, we provide a detailed point-by-point response.

 

Reviewer 1

Open Review Comments and Suggestions for Authors

Major Comment 1

Reviewer comment:
Authors should emphasize a clear distinction between malignant B cells and tumor-infiltrating B cells and those two malignancies should be addressed in separate sections (B cell lymphomas/leukemias).

Response:
We thank the reviewer for this very important suggestion. We agree that the earlier version of the manuscript did not sufficiently distinguish between non-malignant tumor-infiltrating B cells in other tumors and malignant B cells in hematologic malignancies. In the revised manuscript, we have substantially reorganized the review to address these as two clearly separated biological contexts.

 

Major Comment 2

Reviewer comment:
The therapeutic section should be followed by an extensive section on the safety measures and toxicity discussions. Authors should provide a table of structures current clinical trials (NCT numbers/trial phase specifics/enrollment numbers/efficacy/safety data/completed and ongoing trials).

Response:
We thank the reviewer for this valuable recommendation. In response, we have reorganized section 6 as two sections 6.1 and 6.2 highlighting therapeutic targeting of malignant B cells in comparison to existing strategies to target the non-malignant tumor infiltrating B cells in TME.

Major Comment 3

Reviewer comment:
Authors should include a section describing how the review was performed, how many studies supporting /not supporting stated claims.

Response:
We appreciate this helpful suggestion. To improve transparency, we have added a details in the last paragraph in introduction section about how the review was conducted and the scope of this work as suggested by the reviewer.

Major Comment 4

Reviewer comment:
Authors have to be clearer in discussing murine and human data to highlight similarities and differences in murine vs human biology.

Response:
We thank the reviewer for raising this important point. In the revised manuscript, we have carefully revisited the text and now explicitly identify whether findings derive from human or mouse or both.

 

Minor Comment

Reviewer comment:
Please in the graphical abstract, select different background; the light green is difficult to read.

Response:
We thank the reviewer for this helpful suggestion. The graphical abstract has been revised to enhance readability.

Reviewer 2 Report

Comments and Suggestions for Authors

Overall Assessment

This review illustrates a relevant topic: how metabolic constraints within the tumor microenvironment influence B-cell fate and function. The authors covered important pathways: glycolysis/OXPHOS, lipid and amino acid metabolism, hypoxia and lactate signaling, and kynurenine/AhR pathways.

That said, the manuscript would benefit from substantial reorganization. At present, it moves back and forth between (i) normal B-cell immunometabolism, (ii) non-malignant tumor-infiltrating B cells in solid tumors, and (iii) malignant B-cell metabolism (e.g., lymphoma, myeloma), without clearly separating these contexts. This makes the conceptual flow difficult to follow.

For these reasons, I would recommend major revision to improve conceptual organization.

Major Comments

1. Separation of non-malignant vs malignant B cells

An important aspect relies in the conflation of non-malignant tumor-infiltrating B cells (TIBs) and malignant B cells. Sections 3–6 alternate between discussing B cells in solid tumor microenvironments and intrinsic metabolic rewiring in B-cell malignancies (e.g., DLBCL, CLL, B-ALL, myeloma). These are biologically distinct settings with different drivers of metabolic change.

Figure 2 adds to the confusion. Its title refers to “metabolic reprogramming of malignant B cells,” yet it appears in a section primarily discussing TME effects on infiltrating immune B cells. As currently structured, this is likely to mislead readers.

I suggest reorganizing it into two sections:

• Non-malignant B cells in solid tumor TMEs (TLS/GC-like B cells, plasma cells, Bregs, metabolic competition, lactate, hypoxia, adenosine, kynurenine, lipid availability).
• Malignant B cells (Warburg phenotype, OxPhos- vs BCR-DLBCL subsets, glutamine, fatty acid metabolism, epigenetic drivers).

A section that connects shared versus distinct metabolic aspects could clear the path later for therapeutic implications.

2. Overly categorical statements

A few statements could be viewed to less implicate universality and make it model dependent.

For example:

• The claim that T cells are the majority infiltrating population and B cells are a minor fraction varies significantly by tumor type, TLS presence, stage, and profiling method.
• The suggestion that activated B cells deplete glucose and oxygen and contribute to lactic acidosis that dampens T-cell responses may be valid in some settings, but activated B cells—especially in TLS contexts—are often associated with improved prognosis.

Strong mechanistic claims should be directly tied to key primary studies rather than only general reviews.

3. Mechanistic clarity in Section 2

Depending on the public that will read it, certain statements could create confusion. For example, the statement that “glucose is channeled toward PPP and enhanced glutaminolysis to supply OXPHOS, rather than entering the TCA cycle” reads as contradictory. Glutaminolysis typically feeds the TCA cycle to support OXPHOS. If the idea that glucose carbon is diverted away from mitochondrial oxidation while glutamine fuels TCA/OXPHOS, this could be clearer.

Similarly, statements about fatty acid oxidation in germinal center B cells and memory/plasma cells are presented as broadly established rules. This section should reflect that these models are evolving rather than universally settled.

4. TLS as an underdeveloped organizing framework

TLS and GC-like B cells are introduced early and included in Table 1. The authors could have explored TLS further, including what is known about it (e.g., organization, oxygen gradient, cell population, etc.). Additionally, the authors could clarify the similarities and differences between GC-Like B cells and B cells in TLS regarding metabolism in order to define whether these cells are classical GC B cells or tumor-specific adaptations.

5. Regulatory B-cell metabolism

The section on regulatory B cells would benefit from more careful wording. The manuscript suggests that Bregs tend to rely on oxidative metabolism and lipid utilization to sustain IL-10 production. While there are studies that support this idea, it is probably too broad to present this as a defining metabolic feature of Bregs in general. Regulatory B cells are not a single uniform population. They can arise in response to different stimuli — TLR ligands, CD40 signaling, inflammatory cytokines, hypoxia — and these distinct contexts are likely to shape their metabolic programs differently.

It would help the reader if the authors acknowledged this variability more explicitly. For instance, are the cited studies mainly based on mouse models? In vitro systems? Human tumor samples? Clarifying this would strengthen the section and avoid overgeneralization. If most of the evidence comes from murine models, that should be stated, along with a brief comment on how (or whether) this has been validated in human disease. This is particularly important if the review aims to discuss therapeutic implications.

6. Therapeutic section lacks a decision framework

The therapeutic section is extensive and clearly well researched, but it feels more descriptive than strategic. Many agents and pathways are mentioned, yet it is not always clear how to think about them in a practical or conceptual way.

For example, some approaches seem aimed at reprogramming non-malignant tumor-infiltrating B cells, while others are clearly intended to target malignant B cells directly. These are very different goals, but the manuscript does not consistently distinguish between them. Similarly, if broad metabolic inhibitors are used, what would be the expected impact on beneficial B-cell subsets in tertiary lymphoid structures? Could such approaches inadvertently impair protective humoral responses?

It would strengthen the manuscript to discuss how patients might realistically be stratified if these metabolic strategies were translated into clinical practice. For example, are there measurable features that could guide treatment decisions — such as the presence and organization of TLS, enrichment of Breg-associated markers, expression of key metabolic transporters, or evidence of lactate accumulation or hypoxia within the tumor? Even a brief discussion along these lines would make the therapeutic section feel more clinically grounded and less like a list of potential targets without a clear path forward.

Minor Comments

There are a few language issues throughout the manuscript. Examples include phrases such as “comprises of,” spelling errors like “heterogenous,” and inconsistent capitalization (e.g., germinal center vs Germinal Centre; OxPhos vs OXPHOS).

Figure 2 should either be moved to a section specifically discussing malignant B cells or retitled so that its focus is unambiguous and consistent with the surrounding text.

Finally, the manuscript might benefit from a concise summary table listing key tumor microenvironment metabolites (e.g., glucose, lactate, glutamine, arginine, kynurenine, adenosine, fatty acids) and summarizing their reported effects on different B-cell subsets. This would help readers synthesize a large amount of information more easily.

 

Author Response

Reviewer 2

Overall Assessment

We thank the reviewer for the thoughtful and constructive evaluation. We appreciate the recognition of the relevance of the topic and agree that substantial reorganization was needed to improve conceptual clarity. We have revised the manuscript extensively in response to these comments.

Major Comment 1

Reviewer comment:
Separation of non-malignant vs malignant B cells... Sections 3–6 alternate between discussing B cells in solid tumor microenvironments and intrinsic metabolic rewiring in B-cell malignancies... I suggest reorganizing into two sections...

Response:
We thank the reviewer for this very important suggestion. We agree that the earlier version of the manuscript did not sufficiently distinguish between non-malignant tumor-infiltrating B cells in other tumors and malignant B cells in hematologic malignancies. In the revised manuscript, we have substantially reorganized the review to address these as two clearly separated biological contexts.

 

Major Comment 2

Reviewer comment:
Overly categorical statements... some statements could be viewed to less implicate universality and make it model dependent.

Response:
We appreciate this important observation. We have carefully revised the manuscript to avoid overly broad or categorical statements, especially in contexts where the literature is tumor type-specific, mouse or human model-dependent.

Major Comment 3

Reviewer comment:
Mechanistic clarity in Section 2... the statement that “glucose is channeled toward PPP and enhanced glutaminolysis to supply OXPHOS, rather than entering the TCA cycle” reads as contradictory...

Response:
We thank the reviewer for identifying this point of confusion. We agree that the earlier wording was imprecise. In the revised manuscript, we have revised the sentence as “glucose-derived carbon may be preferentially diverted toward biosynthetic pathways such as the pentose phosphate pathway (PPP), while glutamine-derived carbon can replenish the TCA cycle and support mitochondrial respiration/OXPHOS”. The revised wording now reflects this metabolic distinction more accurately.

 

Major Comment 4

Reviewer comment:
TLS as an underdeveloped organizing framework... authors could have explored TLS further... and clarify similarities and differences between GC-like B cells and B cells in TLS regarding metabolism...

Response:
We thank the reviewer for this excellent suggestion. We agree that tertiary lymphoid structures (TLS) provide an important organizing framework for understanding B-cell states in tumors. Accordingly, we have thoroughly revised the manuscript and made the suggested changes wherever possible.

 

Major Comment 5

Reviewer comment:
Regulatory B-cell metabolism... the manuscript suggests that Bregs tend to rely on oxidative metabolism and lipid utilization... this is probably too broad… Clarify whether studies are murine/in vitro/human.

Response:
We thank the reviewer for raising this important point. In the revised manuscript, we have carefully revisited the text and now explicitly identify whether findings derive from human or mouse or both.

 

Major Comment 6

Reviewer comment:
Therapeutic section lacks a decision framework... distinguish reprogramming non-malignant TIBs vs targeting malignant B cells directly... discuss patient stratification and impact on beneficial TLS B cells.

Response:
We thank the reviewer for this valuable recommendation. In response, we have reorganized section 6 as two sections 6.1 and 6.2 highlighting therapeutic targeting of malignant B cells in comparison to existing strategies to target the non-malignant tumor infiltrating B cells in TME.

Minor Comment 1

Reviewer comment:
There are a few language issues throughout the manuscript... “comprises of,” “heterogenous,” inconsistent capitalization...

Response:
We thank the reviewer for pointing this out. We have now carefully edited the manuscript for grammar, consistency, abbreviation usage throughout the manuscript.

 

Minor Comment 2

Reviewer comment:
Figure 2 should either be moved to a section specifically discussing malignant B cells or retitled...

Response:
We agree and thank the reviewer for this suggestion. Figure 2 has now been revised for improved clarity on malignant B cells vs non-malignant tumor infiltrating B cells.

 

Minor Comment 3

Reviewer comment:
The manuscript might benefit from a concise summary table listing key tumor microenvironment metabolites... and their reported effects on different B-cell subsets.

Response:
We thank the reviewer for this constructive suggestion. As suggested by the reviewer, we have incorporated the suggested changes in the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

this is a very interesting, valuable, significant, and well-written review. It will be of interest to everyone interested not only in B cell biology, but also in TME. 

I think it should be accepted with minor changes.

1. There are English grammar mistakes - i highlighted some of many; please, carefully correct everything
2. A couple of sentences lost their meaning for that reason
3. Some abbreviations are spelled out repeatedly (or, on the contrary, not given, like Ab). TME is introduced at the beginning, then not used at all for a while, then used again. Bregs are explained at least 4 times, etc.
4. There is no such termin as "B-cell directed CRISPR approaches"... Please give a better explanation for the use of CRISPR platform in the contest of B cell plasticity in TME

Other than that, i really enjoyed reading your manuscript

 

Good luck!

Comments for author File: Comments.pdf

Comments on the Quality of English Language

The quality of english language must be improved

Author Response

Reviewer 3

We thank the reviewer for the positive assessment of our work and for the helpful suggestions.

 

Comment 1

Reviewer comment:
There are English grammar mistakes - I highlighted some of many; please, carefully correct everything.

Response:
We thank the reviewer for pointing this out. The manuscript has been thoroughly edited for grammar, syntax, and readability. We carefully reviewed the full text and corrected the highlighted errors as well as additional language issues identified during revision.

 

Comment 2

Reviewer comment:
A couple of sentences lost their meaning for that reason.

Response:
We appreciate this observation. We have revised the affected sentences for clarity and precision so that their intended meaning is now preserved. We also undertook a broader language revision across the manuscript to improve readability and avoid ambiguity.

 

Comment 3

Reviewer comment:
Some abbreviations are spelled out repeatedly (or, on the contrary, not given, like Ab). TME is introduced at the beginning, then not used at all for a while, then used again. Bregs are explained at least 4 times, etc.

Response:
We thank the reviewer for this helpful comment. We have now standardized abbreviation usage throughout the manuscript.

 

Comment 4

Reviewer comment:
There is no such term as "B-cell directed CRISPR approaches"... Please give a better explanation for the use of CRISPR platform in the context of B cell plasticity in TME.

Response:
We thank the reviewer for this important correction. We agree that the original phrase was imprecise. We have removed the term and revised this section to incorporate the distinction between malignant and non-malignant B cells in cancer.

Reviewer 4 Report

Comments and Suggestions for Authors

In this review article titled "Metabolic Reprogramming of B cells in Cancer: Effects of Altered Energetics", the authors review literature on B cell metabolism in the context of cancer. The review is informative and can be revised as below.

1) The authors have gathered information from many articles and listed it in their description but often sections seem disconnected to read. Also, many sections end abruptly such as sections 4 and 5. Instead, the authors could write a summary para for each of these sections so that the readers can walk-away with a general take home message about the topic. 

2) The sections are also very dense in material and can benefit from breaking down into smaller subsections to better orient the reader. For instance, section 3 can be broken down into atypical memory, Bregs, etc. Similar subsections can be implemented in all other sections. 

3) There is a lot of reliance on citations of other review article when the primary literature should have been cited. This occurs at many occasions throughout the manuscript.

4) Line 190 about the relative proportions of B cells in immune infiltrates in any given tumor is context dependent. It can't be generalized based on a couple of studies. 

5) There are a few occasions where studies conducted on other cells have been mentioned as a possible strategy for B cell modulation. For instance, line 448, GLS inhibitor was applied on T cells. The authors should clarify that these inhibitors work on other cell types and they would like to extend this to B cells. In table 2, row 4, inhibitors + Abs can reduce Breg like signaling. The papers show that ibrutinib and idealisib can reduce IL10, there is no reference to Bregs or Breg like signaling. Column 5 references also have no mention of Bregs. Column 3, studies don't mention B cells, the immune cells mentioned here are DCs and T cells.

6) In several lines, the description is not supported by the cited reference. These lines are310-311 (T cell suppression), lines 321-329, 366-367 (B cells reduce MHCII), lines 415-416 (mitochondrial activation and ROS production), 459-467. Please use the appropriate reference or alter the description as per the cited reference.

Author Response

Reviewer 4

We thank the reviewer for the positive evaluation of the manuscript and for the constructive recommendations for improvement.

Comment 1

Reviewer comment:
The authors have gathered information from many articles and listed it in their description but often sections seem disconnected to read. Also, many sections end abruptly such as sections 4 and 5. Instead, the authors could write a summary para for each of these sections...

Response:
We appreciate this helpful suggestion. In the revised manuscript, we have improved transitions between sections and added a summary concluding the sections.

 

Comment 2

Reviewer comment:
The sections are also very dense in material and can benefit from breaking down into smaller subsections...

Response:
We agree and thank the reviewer for this recommendation. In response, we have reorganized section 6 as two sections 6.1 and 6.2 highlighting therapeutic targeting of malignant B cells in comparison to existing strategies to target the non-malignant tumor infiltrating B cells in TME.

 

Comment 3

Reviewer comment:
There is a lot of reliance on citations of other review article when the primary literature should have been cited.

Response:
We thank the reviewer for highlighting this important issue. We have carefully re-examined the citations throughout the manuscript and added numerous primary research articles wherever required.

 

Comment 4

Reviewer comment:
Line 190 about the relative proportions of B cells in immune infiltrates in any given tumor is context dependent. It can't be generalized based on a couple of studies.

Response:
We agree with the reviewer and have revised this statement to avoid overgeneralization.

 

Comment 5

Reviewer comment:
There are a few occasions where studies conducted on other cells have been mentioned as a possible strategy for B cell modulation... The authors should clarify that these inhibitors work on other cell types and they would like to extend this to B cells...

Response:
We thank the reviewer for this careful and important observation. We have now revised the therapeutic section based on the target malignant cells and non-malignant cells in the TME.

Comment 6

Reviewer comment:
In several lines, the description is not supported by the cited reference... Please use the appropriate reference or alter the description as per the cited reference.

Response:
We are grateful to the reviewer for identifying these discrepancies. We carefully rechecked all of the citations and revised the affected text accordingly with addition of primary research articles.  

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Sarkar et al have carefully addressed my comments. I am thanking authors for their hard work and recommend accepting this manuscript in current form.

Author Response

We would like to thank the reviewer for careful evaluation in round 2 and we have made the necessary changes as suggested in the revised manuscript.