Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

It is my pleasure to review this manuscript which is titled “Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects”. The author tried to summarize the broad and potent applications of bioengineered MSCs in solid tumors targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.

However, here are some issues worth noting.

1.           The authors elaborate on the modification of "tumor targeting" based on the advantages of MSCs, including the three major applications of MSCs as therapeutic cell carriers: therapeutic drugs and bioactive molecules, oncolytic viruses, and suicide genes, and studies to enhance the homing of MSCs to tumor sites are discussed in detail. However, there is a lack of discussion on how to improve the shortcomings of MSCs "may promote tumor growth by supporting angiogenesis, modulating the immune environment, and increasing the aggressiveness of cancer stem cells."

2.           In the layout of the review: "2.2. Enhancement of MSC homing to tumor site" should be classified in section 2.1, and "MSC-derived extracellular vesicles" should be in section 2.2.

3.           Figure 1 Legend should be a simple description of Figure 1, not just a title.

Author Response

It is my pleasure to review this manuscript which is titled “Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects”. The author tried to summarize the broad and potent applications of bioengineered MSCs in solid tumors targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.

However, here are some issues worth noting.

Reply: Thank you very much for your kind comments. We have tried to answer each of your points as follows:

1. The authors elaborate on the modification of "tumor targeting" based on the advantages of MSCs, including the three major applications of MSCs as therapeutic cell carriers: therapeutic drugs and bioactive molecules, oncolytic viruses, and suicide genes, and studies to enhance the homing of MSCs to tumor sites are discussed in detail. However, there is a lack of discussion on how to improve the shortcomings of MSCs "may promote tumor growth by supporting angiogenesis, modulating the immune environment, and increasing the aggressiveness of cancer stem cells."

Reply: We agree with the referee’s  because in the tumour microenvironment, MSCs can act as anti-tumoral agents but also to favor tumour development. Accordingly, it appears interesting to comment all possible effects of MSCs in the tumour niches, including those indicated by the referee (i.e., angiogenesis, modulation of immune responses, and increase of cancer stem cell aggressiveness). Therefore, we have included additional information in the text that show other solutions to  mitigate the inhibitory effects of MSCs on the immune system against tumours, and on the viability of cancer stem cells (see sections 2.2 and 2.3.1). Information on MSC modifications for preventing tumour angiogenesis had been  previously discussed in section 2.3.1 (lines 448-450).

2. In the layout of the review: "2.2. Enhancement of MSC homing to tumor site" should be classified in section 2.1, and "MSC-derived extracellular vesicles" should be in section 2.2.

Reply: As suggested, the two sections have been rearranged.

3. Figure 1 Legend should be a simple description of Figure 1, not just a title.

Reply: In agreement with the referee’s suggestion, we have added the appropriate description to the legend of Figure 1.

Reviewer 2 Report

Comments and Suggestions for Authors

Please see the attachment

Comments for author File: Comments.pdf

Comments on the Quality of English Language

The english used is correct

Author Response

In this review, the authors highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. They discuss the potential of MSC-derived extracellular vesicles to improve drug/molecule delivery efficiency to cancer cells. They also reported ongoing clinical trials evaluating the MSC therapeutic potential. The authors described the different strategies to enhance the anti-tumour properties of both MSCs and MSC-EVs.

The authors present a well written, scientifically sound review article that details the use of MSCs and EVs as the next-generation nanocarriers and therapeutic agents in the evolving field of cancer therapy. The authors identified 212 articles of interest.

I think this review will be helpful for readers of biomolecules. The authors can consider following suggestions to improve the review.

Reply: Thank you very much for your kind comments. We have answered each of your comments below.

In  terms  of  the  treatment  of  cancer,  the  roles  of  MSCs  are  divergent.  Numerous  studies  have demonstrated that MSCs have pro-tumor functions. However, MSCs can also inhibit the growth of tumors through a multitude of mechanisms. The authors should describe in a table or in a schematic representation the tumor promotive and inhibitory roles of MSCs with appropriate references.

Reply: In agreement with  the reviewer’s comment, we have included a new figure (see Figure 1) on the pro- and anti-tumour roles of MSCs in cancer biology.

There are literature reviews published on this topic which showcase the use of MSCs/EVs for delivery of drugs and therapeutics, the authors have not cited the recently published works in their article. They need to include and acknowledge the work that is already done and differentiate how their work is novel (Weng Z et al, J Hemato Oncol 2021; Takayama Y et al, Expert Opin Drug Deliv 2021; Hamilton G et al, Expert Opin Biol Ther 2022; Taeb S et al, Curr Mol Med 2024; Taeb S et al, Curr Top Med Chem 2024; Song Y et al, Front Oncol 2024).

Reply: Thank you very much for your suggestion. Accordingly, these new references have been included in different parts of the new version of the manuscript.

MSCs and EVs can be loaded with therapeutic agents and used for tissue regeneration and cancer therapeutics. The principal methods for loading cargo in MSCs and EVs should be described as well as the pharmaceutical ingredient or cargo loaded.

Reply: Thank you very much. We have included a brief description on the more commonly used methods for modifying MSCs and MSC-EVs (see in the revised manuscript: sections 2.3.1 and 2.2, respectively).

Like the MSCs from which they are derived, EVs can either suppress or promote tumor growth. The pro- and anti-tumorigenic activity of MSC-EVs on different types of cancers should be described as well as their mechanisms.

Reply:  As suggested by the reviewer, we have included  some information on the role of MSC-EVs in supporting  tumour progression ( see section 2.2).

Taheri M et al described recently the bioengineering approaches to improve the potency of MSC as an off-the-shelf versatile tumor delivery vehicle. This article should be added in the references.

Reply: Thank you very much. The suggested reference has been included in the introduction section of the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

High-quality review on the use of bioengineered MSCs in Anti-Cancer therapy. Four different strategies and procedures of enhanced targeting and homing are systematically described and discussed. The effect of different sources is contrasted, including widely used bone marrow or adipose tissue, amniotic membrane, or Wharton's jelly. Moreover, ongoing clinical trials are evaluated for their therapeutic potential and future MSCs-based treatment. More than 210 sources are cited in the work. These sources are mostly recent (<10 years). The English is at a high level. The manuscript is easy to read and clear to understand. 

Author Response

High-quality review on the use of bioengineered MSCs in Anti-Cancer therapy. Four different strategies and procedures of enhanced targeting and homing are systematically described and discussed. The effect of different sources is contrasted, including widely used bone marrow or adipose tissue, amniotic membrane, or Wharton's jelly. Moreover, ongoing clinical trials are evaluated for their therapeutic potential and future MSCs-based treatment. More than 210 sources are cited in the work. These sources are mostly recent (<10 years). The English is at a high level. The manuscript is easy to read and clear to understand. 

Reply: Thank you very much. We appreciate the critical feedback from the reviewer.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors did the necessary changes. I have no other suggestion.