Magnetic Fields as Biophysical Modulators of Anticancer Drug Action

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review addresses an emerging and relevant topic: the role of static and extremely low-frequency magnetic fields (SMFs, ELF-EMFs) in modulating anticancer drug responses. It compiles extensive literature across chemotherapy, targeted therapy, and supportive agents, while also covering mechanistic insights (membrane transport, oxidative stress, apoptosis, cell cycle effects). The manuscript demonstrates comprehensive data gathering and potential significance for translational oncology.

However, the methodology underpinning the literature selection is unclear, and the results are often presented descriptively (tables and listings) rather than critically synthesized. Clinical translation is noted but not deeply integrated into the discussion. For clarity, reproducibility, and impact, the review requires significant revision.

 Major Comments

1. The review does not state how studies were identified (databases searched, inclusion/exclusion criteria, date ranges). This omission reduces transparency.
2. A brief “Methods” section should be added to explain the literature search and classification process.

3. Results are divided by drug type and field exposure, but the text repeats details already in tables. Consider restructuring: Group findings into synergistic, antagonistic, and neutral outcomes. Then analyze by drug classes (platinum agents, anthracyclines, targeted therapies).This would avoid redundancy and improve the flow.

4. Tables are exhaustive but overwhelming. They present endpoints without commentary on reproducibility, quality, or clinical significance. What cell-type or parameter factors explain antagonism?

5. The authors should compare and contrast findings, e.g.: Why do SMFs potentiate cisplatin in some studies but not others?

    

6. Which results are robust across multiple models?
7.  

8. The mechanistic section (membrane, ROS, cell cycle, apoptosis) is informative but reads as parallel descriptions. Stronger integration is needed to explain how these mechanisms interrelate and explain the diverse experimental results. Also see https://doi.org/10.1088/1361-6528/aaaea9, https://doi.org/10.3390/pharmaceutics15071871 

9. The clinical studies section is very brief compared to preclinical coverage. Since translational impact is a central motivation, more discussion is needed: What lessons can be learned from failed or inconclusive trials? What field strengths/frequencies are technically feasible in patients? Where are the safety boundaries?

10. Results are highly heterogeneous; some show synergy, others antagonism. The review would be stronger if it highlighted systematic patterns (e.g., frequency/intensity “windows”) rather than listing studies in isolation.

Minor Comments

Abstract: Too long; should emphasize novelty and key unresolved issues.

Figures: Add a schematic figure summarizing key drug–MF interaction pathways (instead of dense text-only explanations).

Tables: Consider splitting large tables into supplementary material, leaving only condensed versions in the main text.

Language: Needs refinement; avoid phrases like “it can be found that” and ensure consistency in tense.

 

Author Response

Response to Reviewer

We sincerely appreciate the reviewer’s thorough and constructive evaluation of our manuscript. Your insightful comments have greatly helped us to identify key areas for clarification and improvement. We carefully considered each point and have revised the manuscript accordingly to enhance its scientific rigor, clarity, and overall impact. (We would like to clarify that in the reviewer’s feedback, several comment numbers were left blank or addressed overlapping issues. For clarity and conciseness, we have merged related comments into unified responses while maintaining the logical sequence of the original review.)

Major Comments

Comment 1 & 2:
The review does not state how studies were identified (databases searched, inclusion/exclusion criteria, date ranges). This omission reduces transparency. A brief “Methods” section should be added to explain the literature search and classification process.

Response:
We appreciate this important suggestion. A new Methods section has been added after the Introduction. It describes our literature search strategy (databases: PubMed, Web of Science, Scopus), time frame (1996–2025), keywords (“static magnetic field”, “extremely low-frequency electromagnetic field”, “anticancer drug”, “chemotherapy”, “targeted therapy”), and inclusion/exclusion criteria (peer-reviewed original research, focus on MF–drug interactions).

Comment 3:
Results are divided by drug type and field exposure, but the text repeats details already in tables. Consider restructuring: Group findings into synergistic, antagonistic, and neutral outcomes.

Response:
We thank the reviewer for this comment. Because our review focuses on combined effects of magnetic fields with chemotherapy, we structured the literature first by field type (SMFs and ELF-EMFs) and then by drug class, followed by the observed biological outcome (synergistic, antagonistic, or neutral). This approach is consistent with previous reviews in the field and preserves clarity regarding the biological differences between SMFs and ELF-EMFs. To address redundancy, we revised the tables: studies with consistent findings are grouped together, while inconsistent results are clearly separated. This adjustment improves readability and highlights reproducibility.

Comment 4, 5 & 6:
Tables are exhaustive but overwhelming. They present endpoints without commentary on reproducibility, quality, or clinical significance. Why do SMFs potentiate cisplatin in some studies but not others? Which results are robust across models?

Response:
We appreciate the reviewer’s insightful comments. We agree that the tables are extensive; however, they summarize essential experimental parameters compiled from multiple studies, which we believe are valuable for cross-comparison and future replication. We will revise the tables to make them more concise and easier to read while preserving key information.

Regarding the variable outcomes of SMF–cisplatin co-treatment, we have discussed in the revised manuscript that these discrepancies likely arise from differences in cell type, magnetic field intensity, and exposure duration. Further systematic studies are needed to clarify these factors and establish more consistent conclusions. We hope that this review will encourage additional work toward that goal.

Comment 7 & 8:
The mechanistic section (membrane, ROS, cell cycle, apoptosis) is informative but reads as parallel descriptions. Stronger integration is needed to explain how these mechanisms interrelate and explain the diverse experimental results. Also see https://doi.org/10.1088/1361-6528/aaaea9, https://doi.org/10.3390/pharmaceutics15071871

Response:
We sincerely thank the reviewer for this valuable suggestion. We agree that the original mechanistic section may have appeared as parallel descriptions. In fact, as noted at the end of Section 5.4, our intent was to emphasize that these mechanisms are interrelated rather than independent, but this was not sufficiently clear. To address this, we have revised the text to highlight the mechanistic crosstalk more explicitly (Sections 5.1–5.4) and added a new subsection, “5.5 Integration and Crosstalk.” This subsection summarizes how membrane alterations, redox modulation, cell cycle perturbation, and apoptosis are interconnected, with apoptosis serving as a downstream integration point. We believe these revisions improve coherence and provide a stronger mechanistic framework, in line with the reviewer’s recommendation.

Comment 9:
The clinical studies section is very brief compared to preclinical coverage. Since translational impact is a central motivation, more discussion is needed: What lessons can be learned from failed or inconclusive trials? What field strengths/frequencies are technically feasible in patients? Where are the safety boundaries?

Response:
We agree. However, as only three clinical studies exist in this field, the scope is inherently limited. We have expanded the section by discussing feasibility of field strengths and frequencies in clinical practice, reported safety data, and possible reasons for inconclusive outcomes (e.g., small sample size, heterogeneity of patient population). We now emphasize that further well-designed clinical studies are required before translation to practice.

Comment 10:
Results are highly heterogeneous; some show synergy, others antagonism. The review would be stronger if it highlighted systematic patterns (e.g., frequency/intensity “windows”) rather than listing studies in isolation.

Response:
We appreciate the reviewer’s insightful observation regarding the heterogeneity of the reported results. Indeed, studies investigating magnetic field–drug interactions often yield variable outcomes, including synergistic, antagonistic, or neutral effects. This variability largely reflects the diversity in experimental conditions—such as field intensity, frequency, exposure duration, drug type, and cell model—which makes it challenging to define consistent “window” effects across studies.

In our review, we aimed to objectively summarize the available data rather than reinterpret or overgeneralize findings beyond the evidence presented. To assist readers in identifying potential systematic patterns, we have organized the tables to group studies with similar trends and highlighted key parameters (e.g., magnetic flux density, exposure duration) that may underlie consistent or divergent results. We agree that identifying reproducible frequency or intensity “windows” remains an important future direction, and we have emphasized this point in the revised Section 6.1.

Minor Comments

1. Abstract:
   Too long; should emphasize novelty and key unresolved issues.

Response:
The Abstract has been shortened, with stronger emphasis on novelty and unresolved issues.

2. Figures:
   Add a schematic figure summarizing key drug–MF interaction pathways (instead of dense text-only explanations).

Response:
We appreciate the reviewer’s suggestion to include a schematic figure summarizing drug–MF interaction pathways. In fact, we have already incorporated a figure (“Mechanistic model of magnetic field-assisted antitumor drugs”) that aims to provide a visual summary of the major mechanisms discussed.

3. Tables:
   Consider splitting large tables into supplementary material, leaving only condensed versions in the main text.

Response:
We thank the reviewer for this valuable comment. The tables were designed to comprehensively present experimental parameters and outcomes, following the practice of several related reviews. Since these details are crucial for understanding the heterogeneity in results, we consider them important to retain. Nevertheless, we agree that readability can be improved, and we will revise the tables to make them more concise and structured.

4. Language:
   Needs refinement; avoid phrases like “it can be found that” and ensure consistency in tense.

Response:
Language has been refined throughout for clarity, tense consistency, and conciseness.

Conclusion:
We once again thank the reviewer for the valuable feedback and thoughtful suggestions. We believe that the revisions and clarifications made in response to your comments have significantly strengthened the manuscript and improved its readability and scientific contribution.

Reviewer 2 Report

Comments and Suggestions for Authors

The concise review “Magnetic Fields as Biophysical Modulators of Anticancer Drug Action” is devoted to the discussion of important problem of elucidating of  physical nature of magnetic field in life of human beings. The presented issue is very complex and is actively studied from numerous points of view. It  was found that low intense magnetic field (MF) participate in generation of reactive oxygen species, gene expression, cell metabolism, membrane transport etc. On cellular level it was shown the influence of weak constant MF on cell synergetic reaction on anticancer drugs. The mechanism of MF action is not clear now. The authors presented numerous experimental results of MF action. Main part of results have being worked in preclinical studies, few results were elaborated in clinical trials. The presented review may be considered as important contribution in understanding the physical principles of interaction MF with life matter. The manuscript has some disadvantages.

Comment 1 . The role of earth magnetic field in life is not discussed in article  at all, but human population, plants and animals were grown under constant influence of earth MF throughout the history of mankind.

Comment 2. How to exclude the influence of weak earth MF in preсise biological experiments?. What protection “walls”  against MF were engineered in practice?

Comment 3. Many people are known to  experience poor health during magnetic storms. What is known about this phenomena and its origin nature? Statistics?

Comment 4. What methods and instruments exist for accurately measuring the magnitude of an internal magnetic field in cells and tissue?

After addition of these  reminded themes the manuscript may be submitted for publication.

Comments on the Quality of English Language

no comment

Author Response

Response to Reviewer

We sincerely thank the reviewer for the constructive and thoughtful comments on our manuscript entitled “Magnetic Fields as Biophysical Modulators of Anticancer Drug Action”. The comments have been very valuable for improving the clarity and completeness of our review. Below, we provide point-by-point responses.

Comment 1

The role of earth magnetic field in life is not discussed in article at all, but human population, plants and animals were grown under constant influence of earth MF throughout the history of mankind.

Response:
We thank the reviewer for this thoughtful comment. Our review specifically focuses on the combined effects of externally applied magnetic fields (SMFs and ELF-EMFs) with antitumor agents. The studies included in our analysis did not report or control for the influence of the Earth’s geomagnetic field. Moreover, all experiments were conducted with proper control groups, ensuring that any observed effects could be attributed to the applied magnetic fields rather than the geomagnetic background.

Comment 2

How to exclude the influence of weak earth MF in precise biological experiments? What protection “walls” against MF were engineered in practice?

Response:
We thank the reviewer for raising this important methodological issue. The influence of the Earth’s geomagnetic field (approximately 50 μT) on laboratory studies can be considered in three aspects:

1. Negligible impact due to intensity difference

The intensity of the geomagnetic field is very weak compared with the static or electromagnetic fields typically applied in laboratory experiments, which usually range from several millitesla to tesla levels—hundreds to thousands of times stronger. Under such circumstances, the geomagnetic field acts as a constant “background noise” that has little relevance to the measured biological outcomes.

2. Controlled by experimental design

Most experimental designs employ untreated control groups that are exposed to the same geomagnetic background as the test groups. Therefore, any observed differences in biological responses are attributed to the applied magnetic fields, while the constant geomagnetic contribution is naturally canceled out by comparison.

3. Specific research contexts where geomagnetic field matters

We acknowledge that the geomagnetic field is not universally negligible. In certain specialized research areas, it is treated as a critical experimental variable. These include:

• Magnetoreception and navigation studies, such as investigations of how birds, turtles, and magnetotactic bacteria utilize the geomagnetic field.
• Hypomagnetic and near-zero field studies, which explore whether organisms exhibit abnormal development, growth, or behavior when shielded from the geomagnetic field.
• Geomagnetic variations and health studies, including epidemiological analyses of correlations between geomagnetic storms and human disease incidence.

In these contexts, researchers actively control or exclude geomagnetic influences using engineered devices such as mu-metal shielding, Helmholtz coils, and hypomagnetic chambers. These approaches allow for precise manipulation of the magnetic environment when the geomagnetic field itself is the variable of interest.

In summary, while the geomagnetic field generally has negligible influence in most cancer-related magnetic field studies due to its weak intensity and the use of proper controls, it becomes central in specialized investigations where weak-field effects are the primary focus.

Comment 3

Many people are known to experience poor health during magnetic storms. What is known about this phenomena and its origin nature? Statistics?

Response:
We thank the reviewer for raising this important point. However, we would like to clarify that the focus of our review is specifically on the interactions between controlled magnetic field exposures and anticancer drug action. Issues such as the health effects of geomagnetic disturbances (“magnetic storms”) fall outside the scope of this article.

In the clinical studies of therapeutic magnetic field applications that we reviewed, no consistent evidence of harmful effects in humans was reported. By contrast, “magnetic storms” refer to transient perturbations of the Earth’s magnetosphere caused by solar activity. Epidemiological studies have suggested possible associations between such geomagnetic disturbances and increased risks of cardiovascular and neurological events [1, 2]. However, these findings are heterogeneous, potentially confounded by environmental factors, and require further investigation to establish causal mechanisms.

[1] Carolina Leticia, Zilli Vieira,Danilo, Alvares,Annelise, Blomberg et al. Geomagnetic disturbances driven by solar activity enhance total and cardiovascular mortality risk in 263 U.S. cities.[J] .Environ Health, 2019, 18: 83.

[2] R W, Kay,Geomagnetic storms: association with incidence of depression as measured by hospital admission.[J] .Br J Psychiatry, 1994, 164: 403-9.

Comment 4

What methods and instruments exist for accurately measuring the magnitude of an internal magnetic field in cells and tissue?

Response:
We thank the reviewer for raising this technical question. Since the primary focus of our review is on the interactions between externally applied magnetic fields and anticancer drugs, we did not include detailed discussion of measurement techniques. Nevertheless, we acknowledge the importance of accurate magnetic field assessment at the cellular and tissue levels. At present, direct measurement of “internal” magnetic fields within cells remains highly challenging. Common approaches include:

1. Magnetometry techniques such as SQUID (superconducting quantum interference devices) and optically pumped magnetometers, which offer ultra-high sensitivity for detecting weak magnetic fields in biological samples.
2. Magnetic resonance–based methods (e.g., NMR, MRI, MRS), which can provide indirect information on magnetic susceptibility and local field distribution within tissues.
3. Microscale sensors including Hall sensors, magnetoresistive sensors, and diamond NV (nitrogen-vacancy) centers, which are being developed for subcellular magnetic field mapping.

These methods are still largely confined to specialized biophysical studies and are not yet routine in biomedical experiments. Importantly, most biological investigations relevant to our review employ externally applied and well-defined magnetic fields, where accurate exposure parameters can be readily controlled without relying on internal field measurement.

Conclusion:

We hope that these revisions satisfactorily address the reviewer’s concerns and improve the quality and scope of our review. We thank the reviewer again for the valuable suggestions.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Authors should cite the references proposed by the reviewer https://doi.org/10.1088/1361-6528/aaaea9, https://doi.org/10.3390/pharmaceutics15071871 

Author Response

Comment:
Authors should cite the references proposed by the reviewer (https://doi.org/10.1088/1361-6528/aaaea9; https://doi.org/10.3390/pharmaceutics15071871).

Response:
We sincerely thank the reviewer for the valuable suggestion and for recommending the two references (https://doi.org/10.1088/1361-6528/aaaea9; https://doi.org/10.3390/pharmaceutics15071871). After carefully reviewing both papers, we found that they primarily investigate magnetic nanoparticles (MNPs) and their effects on drug delivery and cellular function.

However, our review specifically addresses the biological and pharmacological effects of externally applied magnetic fields—particularly static magnetic fields (SMFs) and extremely low-frequency electromagnetic fields (ELF-EMFs)—in the absence of magnetic materials. Including studies based on MNPs would introduce different mechanisms and confounding physicochemical factors (such as particle size, surface charge, and magnetic responsiveness) that lie outside the conceptual and mechanistic scope of our paper.

We fully acknowledge the scientific value of the cited works; however, for the sake of thematic clarity and consistency, we respectfully believe they fall outside the scope of our review.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for attentive answers to the reviewer's comments.I wish you success in continuing your work in biological action of magnetic field.

Comments on the Quality of English Language

no comment

Author Response

Response:

We sincerely thank the reviewer for their kind words and encouragement. We greatly appreciate the time and effort devoted to reviewing our work and for the constructive feedback provided during the revision process. Your comments have been very helpful in improving the quality and clarity of our manuscript.