Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review discussed using nanoparticle-generated tumor biological amplification as a potentially exchangeable margin to reduce selected components of physical, spatial, or temporal radiation exposure while preserving tumor control and immunogenicity. The manuscript is well structured. Please address the following issues before considering publication.  

1. Please address how the figures were generated and make sure it confirms the journal's requirement for using AI tools.
2. The last few sections are repetitive in disclaiming concepts like dose exchange, biodistribution measurement,  and multicompartment immune preservation. Please condense them. 
3. Different nanoparticle platforms produce radioenhancement through fundamentally different mechanisms, and this heterogeneity should be addressed more explicitly and cautiously.
4.  Please clarify the proposed seven-dimensional immune-dose-shaping framework.

Author Response

 Response to Reviewer 1

 Comment 1. Please address how the figures were generated and make sure it confirms the journal's requirement for using AI tools.

Response: Thank you for highlighting this issue. We have clarified the generation and preparation of all conceptual figures and made the disclosure consistent throughout the manuscript. Figures 1–4 were created using Canva Magic Design for visual design and graphical organization. The scientific concepts, terminology, relationships between elements, and interpretation shown in the figures were defined and verified by the authors; no experimental data, research results, or primary scientific images were generated or modified using this tool. We have revised the legends of Figures 1–4 accordingly and expanded the statement in the Acknowledgments section to provide a transparent disclosure of the tool's use. The authors reviewed and edited all graphical outputs and take full responsibility for their final content.

Revised text: Acknowledgments: lines 788-794; Legends of Figures 1-4.

Comment 2. The last few sections are repetitive in disclaiming concepts like dose exchange, biodistribution measurement, and multicompartment immune preservation. Please condense them.

Response: We thank the reviewer for this insightful comment. The manuscript intentionally emphasized these boundaries because the proposed framework is hypothesis-generating, but this resulted in unnecessary repetition in the later sections. We have therefore centralized the complete experimental proof standard in Section 9.6 and Table 5, where tumor isoeffect, preserved immunogenicity, multicompartment immune preservation, immune-relevant dosimetry, and nanoparticle biodistribution are defined together. Subsequent sections now refer back to this framework rather than restating the same criteria in full. We also condensed the Translational Boundary, Limitations, and Conclusion sections to reduce repeated discussion of dose exchange, biodistribution, and multicompartment immune preservation while retaining the key translational and safety boundaries.

Revised/condensed text in: Section 11 lines 637-642; Section 13 lines 725-733; Conclusions lines 761-766.

Comment 3. Different nanoparticle platforms produce radioenhancement through fundamentally different mechanisms, and this heterogeneity should be addressed more explicitly and cautiously.

Response: We thank the reviewer for raising this important issue. Although Section 5 was already organized according to major mechanistic classes of nanoparticle radioenhancement, we have now added an explicit synthesis paragraph emphasizing that the resulting amplification margin cannot be assumed to be equivalent or transferable across nanoparticle platforms. The revised text distinguishes predominantly physical high-Z enhancement from redox-, hypoxia-, DNA-repair-, metabolic-, and immune-mediated mechanisms and notes that hybrid systems may combine several pathways. We further clarify that the magnitude and reproducibility of any proposed dose-exchange margin must therefore be established separately for each nanoparticle–radiotherapy combination rather than extrapolated across mechanistic classes.

Added paragraph in Section 5.5 lines 99-109.

Comment 4. Please clarify the proposed seven-dimensional immune-dose-shaping framework.

Response: We thank the reviewer for raising this important issue and we agree that this point required further clarification. We have clarified the conceptual meaning of the seven-dimensional framework in Section 6.5 and in the legend to Figure 2. We now explicitly state that the seven dimensions—physical dose, volume/spatial exposure, distributed low-dose exposure, marrow dose, geometry/modality, fractionation, and temporal/delivery exposure—are interacting and partially coupled rather than independent or mathematically interchangeable variables. Modification of one dimension may alter several others simultaneously. We also clarify that “exchange” refers to a testable redistribution of treatment exposure made possible by a quantified nanoparticle-generated amplification margin under a prespecified tumor-isoeffect constraint, and does not imply conservation of a single physical or biological quantity or a fixed conversion factor between dimensions.

Added paragraph in: Section 6.5. lines 122-132; added text in Figures 2 legend lines 175-177.

 

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to the authors

The authors, Lunca et al., have provided a comprehensive review entitled “Nanoparticle-Enabled Immune-Dose Shaping in Breast Cancer Radiotherapy: Reconciling Tumor Immunogenicity with Systemic Immune Preservation.” The manuscript is extensive and provides a detailed discussion of recent advances in the field. However, several aspects could be further clarified or strengthened. Some specific suggestions are provided below:

1. Influence of radiation modality and fractionation: The authors should discuss the effects of radiation modality and fractionation in greater detail, as these parameters can independently influence treatment-related lymphopenia, tumor immunogenicity, and normal-tissue exposure. A clearer discussion of how different radiation modalities and fractionation schemes interact with nanoparticle-based radioenhancement would further strengthen the manuscript.
2. Clarification of the proposed framework: The manuscript should consistently emphasize that the proposed framework is hypothesis-generating and conceptual in nature. The authors should clearly distinguish this framework from clinically validated approaches for nanoparticle-enabled radiation dose reduction to avoid overstating the current level of clinical evidence.

Author Response

Response to Reviewer 2

 Comment 1. Influence of radiation modality and fractionation. The authors should discuss the effects of radiation modality and fractionation in greater detail, as these parameters can independently influence treatment-related lymphopenia, tumor immunogenicity, and normal-tissue exposure. A clearer discussion of how different radiation modalities and fractionation schemes interact with nanoparticle-based radioenhancement would further strengthen the manuscript.

Response: We agree and have expanded Sections 6.2 and 6.3 to distinguish the independent effects of radiation modality and fractionation from their potential interactions with nanoparticle radioenhancement. The revised text now discusses how modality can alter integral dose, low-dose spread, lymphoid and marrow exposure, while also influencing high-Z nanoparticle enhancement through beam-quality and energy dependence. We further clarify that fraction number, dose per fraction, treatment sequence, and timing can independently influence lymphocyte exposure and tumor immunogenicity and may also modify the magnitude or persistence of nanoparticle-mediated radioenhancement. Accordingly, we now emphasize that a nanoparticle amplification margin should be quantified under the same beam quality, modality, fractionation, and delivery conditions in which immune-dose shaping is subsequently evaluated.

Added text in: Section 6 lines 6-9; Section 6.2. lines 44-56; Section 6.3. lines 75-91.

Comment 2. Clarification of the proposed framework. The manuscript should consistently emphasize that the proposed framework is hypothesis-generating and conceptual in nature. The authors should clearly distinguish this framework from clinically validated approaches for nanoparticle-enabled radiation dose reduction to avoid overstating the current level of clinical evidence.

Response: We agree that this point required further clarification. We have strengthened this distinction at the principal points where the framework is introduced and operationalized. In Section 6.5, we now explicitly state that the seven-dimensional immune-dose-shaping framework is conceptual and hypothesis-generating and does not represent a clinically validated dose-reduction strategy or establish treatment-planning constraints. In Section 9.6, we clarify that the five-component proof standard is proposed as an experimental framework rather than an established clinical criterion, and in Section 10 we specify that the staged translational pathway represents proposed research-development steps rather than validated criteria for clinical radiation de-escalation. We have retained the corresponding qualification in the Abstract, Figure 2, Table 1, and Conclusion while avoiding unnecessary repetition elsewhere.

Added text in: Section 1 lines 101-107; Section 6.5. lines 133-136; Section 9.6. lines 419-422; Section 10 lines 481-483.