Review Reports - Overcoming Immunotherapy Resistance in Small-Cell Lung Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an important and timely topic and contains useful trial compilation. However, it requires substantive improvement in scientific rigor, internal consistency, critical appraisal, and language/presentation before it can be considered publishable.

1) Unclear review scope and selection logic

While I agree that a narrative review does not need a systematic-review database protocol, the manuscript still needs a clear scope statement: what the authors intended to cover (e.g., mechanisms + therapeutic strategies; line-of-therapy boundaries; whether only SCLC or broader neuroendocrine carcinomas; whether abstracts/conference reports are included). As written, the inclusion of studies appears opportunistic, and the reader cannot tell what is intentionally excluded or why. Add a concise “Scope and approach” paragraph stating boundaries (disease setting, time horizon, evidence types allowed, and how “key trials” were chosen).

2) Insufficient critical appraisal: compilation dominates over evaluation

The review often lists trials (ORR/DCR/mPFS/mOS) without structured critique of:

trial design limitations (single-arm vs randomized),
patient selection (prior therapies, brain metastases, refractory vs sensitive relapse),
endpoint interpretability (ORR vs OS; investigator vs blinded independent review),
cross-trial non-comparability.

This reduces the manuscript to a catalogue rather than a high-value synthesis.

For each major therapeutic class (BiTEs, ADCs, IO+antiangiogenic, PARPi+IO, RT+IO, adoptive therapies), include a short subsection: “What we can conclude / What we cannot conclude / Key uncertainties”.

3) Internal inconsistency in mechanistic narrative (TMB, immunogenicity, and predictive biomarkers)

The manuscript correctly notes that SCLC often has high TMB yet shows limited ICI benefit, but the discussion does not consistently separate:

immunogenic potential (neoantigen load) from
effective antigen presentation (MHC-I expression, processing machinery) and
functional immune infiltration/exhaustion.

Similarly, statements about “predictive potential” of biomarkers are sometimes asserted without clearly specifying whether the evidence is exploratory, hypothesis-generating, or validated.

Introduce a simple conceptual model (e.g., “neoantigens, presentation, infiltration, effector function, checkpoint dependency”) and place each biomarker/mechanism on that pathway.

4) Subtype framework is introduced but not operationalized for therapy selection

The SCLC molecular subtype framework (ASCL1/NEUROD1/POU2F3/inflamed) is a strength, but the manuscript does not convert it into practical or testable implications:

Which interventions are hypothesized to work best in which subtype?
Are there prospective or retrospective data supporting subtype-specific benefit?
How could subtype assignment be done in practice (even conceptually)?

Add a “Subtype-informed therapeutic hypotheses” table: subtype, immune phenotype, plausible vulnerabilities ,therapies under evaluation.

5) Overstatement of “promising” signals without calibration to evidence strength

Several early-phase results are described as “promising” based on high ORR/DCR, but without adequate caution about:

small sample sizes,
immature survival follow-up,
selection bias and response-evaluable populations,
regression-to-the-mean in later trials.

Use calibrated language: “early signal”, “preliminary activity”, “requires randomized confirmation”. Reserve “practice-changing” only for robust comparative evidence.

6) Trial reporting lacks standardization and sometimes omits context needed for interpretation

Across the manuscript and tables, key contextual elements are inconsistently reported:

line of therapy (1L maintenance vs 2L vs later),
platinum-sensitive vs refractory disease,
proportion previously exposed to IO,
CNS metastasis inclusion/exclusion,
comparator regimen definition in randomized trials.

Standardize trial summaries to a uniform template (Population/Setting; Prior IO; Comparator; Primary endpoint; Key outcomes; Notable toxicities/limitations).

7) Safety/toxicity discussion is underdeveloped relative to efficacy claims

For immuno-engagers and ADCs, toxicity is often briefly listed, but the clinical impact is not synthesized:

dose-limiting toxicities and dose modifications,
discontinuation rates,
toxicity patterns that may limit sequencing/combination,
class-specific safety issues that affect real-world feasibility.

Add a short “Toxicity and feasibility” section for each class and a final integrative paragraph on sequencing constraints driven by safety.

8) Resistance to novel modalities is mentioned but not deeply analyzed

The manuscript raises resistance mechanisms to DLL3 targeting (e.g., on-target resistance), but does not systematically address:

antigen heterogeneity and antigen loss,
lineage plasticity and Notch pathway dynamics,
mechanisms of resistance to topoisomerase payload ADCs (cross-resistance),
implications for retreatment and combination strategies.

Add a dedicated section: “Resistance to emerging therapies (BiTEs/ADCs/cellular therapies): mechanisms and rational combinations”.

9) Clinical translation: sequencing and decision-making remain unclear

The reader is left without an integrated, clinically oriented synthesis:

How should these therapies be sequenced after first-line chemo-IO?
Where do BiTEs vs ADCs best fit?
What is the role of radiotherapy combinations (consolidation vs sensitization)?
What evidence supports combinations vs monotherapy in later lines?

Provide a pragmatic “Current and near-term treatment landscape” figure/algorithm with clear evidence grading (high/moderate/low).

Minor issues

English language and grammar: Numerous awkward constructions and typos (e.g., incorrect prepositions, inconsistent capitalization, misspellings such as “maintainance”, and occasional non-English fragments). The manuscript requires professional English editing.
Editorial placeholders and formatting artifacts: Presence of production placeholders (e.g., incomplete DOI fields, missing editorial metadata), “FOR PEER REVIEW” headers, inconsistent hyphenation and spacing, and table formatting issues. These undermine professionalism and should be fully corrected.
Abbreviation overload and inconsistency: Abbreviations are sometimes introduced without definition or vary across text/tables (e.g., chemotherapy abbreviations, disease stage notation). Provide a single abbreviation list and ensure consistent use.
Numerical reporting consistency: Ensure uniform reporting of medians with confidence intervals, hazard ratios with CI and p-values where applicable, and consistent rounding. Clarify whether endpoints were assessed by investigator or independent review when known.
Mechanistic references: When describing pathways (e.g., epigenetic suppression of antigen presentation), explicitly indicate whether evidence is preclinical, translational correlative, or clinical.

The manuscript has a strong topic and a potentially valuable structure, especially the inclusion of therapeutic classes and trial tables. To reach publishable quality, it must move beyond listing studies and deliver a more critical, standardized, and clinically actionable synthesis, with corrected English and polished presentation.

Author Response

Reviewer 1

1) Unclear review scope and selection logic

Re: We thank the Reviewer for the comment. As stated by the Reviewer, this is a narrative review and a systematic review chart is not needed; generally speaking, all the articles discussed in a narrative review are somewhat “opportunistic”, and the critical review of the articles, the scientific interest to the community is up to the authors. Anyway, we accordingly added 1.1 “Scope and approach” paragraph, in which we better described what is discussed in our manuscript, the purpose of our manuscript and which was our focus on literature.

2) Insufficient critical appraisal: compilation dominates over evaluation

The review often lists trials (ORR/DCR/mPFS/mOS) without structured critique of:

trial design limitations (single-arm vs randomized),
patient selection (prior therapies, brain metastases, refractory vs sensitive relapse),
endpoint interpretability (ORR vs OS; investigator vs blinded independent review),
cross-trial non-comparability.

This reduces the manuscript to a catalogue rather than a high-value synthesis.

Re: We thank the Reviewer for the comment. We agree with the Reviewer that our manuscript could have a more critical appraisal. To address this concern, we re-thought all tables, with new column which report information about the phase study, whether the clinical trial is single arm or randomized, whether patients were immunotherapy pre-treated or immunotherapy-näive, which prior therapy they received; moreover, we added information about the inclusion of brain metastasis or not, as well the primary and secondary endpoints reported. More importantly, we added a column with key limitation for each study, enhancing the critical view for the discussed study. According to other Reviewer’s comment, we also simplified results reported in the Tables to get a more readable and immediate Table. Moreover, at the end of each paragraph, we added a short comment on “what we can/we cannot conclude, by subparagraphs discussing clinical translation of experimental compounds, according to point 9 by this Reviewer (Table 2, 3, 4, 5, paragrahs 3.1.1, 3.2.1, 3.3.1, 3.4.1, 3.5.1, 3.6.1).

3) Internal inconsistency in mechanistic narrative (TMB, immunogenicity, and predictive biomarkers)

The manuscript correctly notes that SCLC often has high TMB yet shows limited ICI benefit, but the discussion does not consistently separate:

immunogenic potential (neoantigen load) from
effective antigen presentation (MHC-I expression, processing machinery) and
functional immune infiltration/exhaustion.

Similarly, statements about “predictive potential” of biomarkers are sometimes asserted without clearly specifying whether the evidence is exploratory, hypothesis-generating, or validated.

Introduce a simple conceptual model (e.g., “neoantigens, presentation, infiltration, effector function, checkpoint dependency”) and place each biomarker/mechanism on that pathway.

Re: We thank the Reviewer for the comment. We agree that a mechanistic view of biomarkers for immunotherapy in SCLC has to be provided to the reader. To address this concern, we added a new Figure (Figure 1) which recapitulates immunotherapy biomarkers for SCLC, indicating which layer of evidence (validated or exploratory) the biomarker covers, and we also contextualized the Figure along the text of our manuscript (lines 456, 681, 973).

4) Subtype framework is introduced but not operationalized for therapy selection

The SCLC molecular subtype framework (ASCL1/NEUROD1/POU2F3/inflamed) is a strength, but the manuscript does not convert it into practical or testable implications:

Which interventions are hypothesized to work best in which subtype?
Are there prospective or retrospective data supporting subtype-specific benefit?
How could subtype assignment be done in practice (even conceptually)?

Add a “Subtype-informed therapeutic hypotheses” table: subtype, immune phenotype, plausible vulnerabilities, therapies under evaluation.

Re: We thank the Reviewer for the comment. Even though our Review is not focused on tumor subtypes and different therapeutic strategies, we agree with the Reviewer that a Table resuming the therapeutic vulnerabilities could enhance the clinical impact and the integration of new approaches with the validated subtypes highlighted to date. In this Table, we highlighted which are the subtype-driven therapeutic approach, and the biological rationale to test new strategies (Table 1).

5) Overstatement of “promising” signals without calibration to evidence strength

Several early-phase results are described as “promising” based on high ORR/DCR, but without adequate caution about:

small sample sizes,
immature survival follow-up,
selection bias and response-evaluable populations,
regression-to-the-mean in later trials.

Use calibrated language: “early signal”, “preliminary activity”, “requires randomized confirmation”. Reserve “practice-changing” only for robust comparative evidence.

Re: We agree with the Reviewer that several early-phase signals were described using language that did not sufficiently calibrate enthusiasm to the level of evidence. We have systematically revised the manuscript to align terminology with trial design, sample size, maturity of follow-up, and presence or absence of comparative data. In particular, we now reserve terms such as “practice-changing” exclusively for randomized trials demonstrating clinically meaningful improvements in survival outcomes, while early-phase, single-arm studies are consistently described as showing “preliminary activity” or “early signals requiring randomized confirmation”. This revision aims to improve scientific rigor and avoid over-interpretation of response-based endpoints (see lines 458, 602, 621, 649, 884, 1123).

6) Trial reporting lacks standardization and sometimes omits context needed for interpretation

Across the manuscript and tables, key contextual elements are inconsistently reported:

line of therapy (1L maintenance vs 2L vs later),
platinum-sensitive vs refractory disease,
proportion previously exposed to IO,
CNS metastasis inclusion/exclusion,
comparator regimen definition in randomized trials.

Standardize trial summaries to a uniform template (Population/Setting; Prior IO; Comparator; Primary endpoint; Key outcomes; Notable toxicities/limitations).

Re: We agree with the Reviewer that interpretation of clinical trial results requires consistent contextual information regarding patient population, prior treatments, and study design. We have therefore revised the manuscript to standardize the reporting of clinical trials across the main text and tables. For each key study, we now explicitly specify line of therapy, prior exposure to immunotherapy, disease sensitivity (when available), CNS metastasis eligibility, comparator regimen in randomized trials, primary endpoint, and major safety limitations. This harmonization aims to facilitate cross-study interpretation while avoiding inappropriate cross-trial comparisons; this accordingly address the point 2 by this Reviewer (Tables 2, 3, 4).

7) Safety/toxicity discussion is underdeveloped relative to efficacy claims

For immuno-engagers and ADCs, toxicity is often briefly listed, but the clinical impact is not synthesized:

dose-limiting toxicities and dose modifications,
discontinuation rates,
toxicity patterns that may limit sequencing/combination,
class-specific safety issues that affect real-world feasibility.

Add a short “Toxicity and feasibility” section for each class and a final integrative paragraph on sequencing constraints driven by safety.

Re: We thank the Reviewer for the comment. We agree that safety constraints have not be underrated when considering new therapeutic strategies. To address this concern, we added, at the end of each paragraph, a short subsection “Toxicity and feasibility considerations” for each major therapeutic class, focusing on dose-limiting toxiticies, discontinuation patterns, and class-specific safety issues. Moreover, we accordingly added a final paragraph summarizing clinical consideration based on safety constraints (see “Toxicity and feasibility considerations paragraphs 3.1, 3.2, 3.3, 3.5, paragraph “3.8 Safety-driven constraints for sequencing and combination strategies”).

8) Resistance to novel modalities is mentioned but not deeply analyzed

The manuscript raises resistance mechanisms to DLL3 targeting (e.g., on-target resistance), but does not systematically address:

antigen heterogeneity and antigen loss,
lineage plasticity and Notch pathway dynamics,
mechanisms of resistance to topoisomerase payload ADCs (cross-resistance),
implications for retreatment and combination strategies.

Add a dedicated section: “Resistance to emerging therapies (BiTEs/ADCs/cellular therapies): mechanisms and rational combinations”.

Re: We thank the Reviewer for the very pertinent comment, underlining which could be the limitations to new treatment approaches led by resistance mechanisms. To address this concern, we added a paragraph discussing which are the known mechanisms of action of resistance mechanism, also providing the rationale for drug combinations to be tested in clinical trials (see paragraph 3.7 Resistance to emerging therapies (BiTEs/ADCs/cellular therapies): mechanisms and rationale for combinations).

9) Clinical translation: sequencing and decision-making remain unclear

The reader is left without an integrated, clinically oriented synthesis:

How should these therapies be sequenced after first-line chemo-IO?
Where do BiTEs vs ADCs best fit?
What is the role of radiotherapy combinations (consolidation vs sensitization)?
What evidence supports combinations vs monotherapy in later lines?

Provide a pragmatic “Current and near-term treatment landscape” figure/algorithm with clear evidence grading (high/moderate/low).

Re: We thank the Reviewer for the insightful comment, highlighting the need for a more integrated and clinically oriented synthesis of therapeutic strategies after the first-line in ES-SCLC.

To address this concern, we have implemented several revisions to the manuscript. At the end of each paragraph, we added a sub-paragraph “Clinical positioning and therapeutic considerations” in which we discuss therapy sequencing, positioning and clinical potential of each approach, as well as the current evidences supporting them (3.1.1, 3.2.1, 3.3.1, 3.4.1, 3.5.1, 3.6.1).

Moreover, we added a new figure (Figure 1), depicting a pragmatic representation of clinical and/or preclinical evidences to address a patient to a specific second-line treatment; the Figure explicitly grades the level of clinical evidence as high, moderate or low, reflecting both available clinical data and existing uncertainties (Figure 1).

Minor issues

English language and grammar: Numerous awkward constructions and typos (e.g., incorrect prepositions, inconsistent capitalization, misspellings such as “maintainance”, and occasional non-English fragments). The manuscript requires professional English editing.

Re: We thank the Reviewer for the comment. We checked the whole manuscript for English typos and we accordingly corrected all of them.

Editorial placeholders and formatting artifacts: Presence of production placeholders (e.g., incomplete DOI fields, missing editorial metadata), “FOR PEER REVIEW” headers, inconsistent hyphenation and spacing, and table formatting issues. These undermine professionalism and should be fully corrected.

Re: We thank the Reviewer for the comment. We guarantee that the manuscript has been uploaded following Editorial instructions. We strongly believe that all Editorial matters will be accordingly addressed before publication.

Abbreviation overload and inconsistency: Abbreviations are sometimes introduced without definition or vary across text/tables (e.g., chemotherapy abbreviations, disease stage notation). Provide a single abbreviation list and ensure consistent use.

Re: We thank the Reviewer for the comment. We have carefully revised the manuscript to ensure consistent and standardized use of abbreviations throughout the text, figures, and tables. All abbreviations are now defined at first occurrence, and a comprehensive List of Abbreviations has been put in alphabetical order as a standalone section.

Numerical reporting consistency: Ensure uniform reporting of medians with confidence intervals, hazard ratios with CI and p-values where applicable, and consistent rounding. Clarify whether endpoints were assessed by investigator or independent review when known.

Re: We thank the Reviewer for this important methodological comment. We have revised the manuscript to ensure uniform numerical reporting across all sections. Median survival outcomes are now consistently reported with 95% confidence intervals as “median X months (95%CI: lower–upper), hazard ratios are presented as HR_XXX X.XX; 95%CI: X.XX–X.XX, with corresponding confidence intervals and p-values when available, and rounding has been standardized throughout the text and tables. Moreover, we clarified the modality of endpoint assessment when reported in the original studies, specifying whether outcomes were investigator-assessed or evaluated by independent blinded central review. These revisions were implemented to improve interpretability and cross-trial contextualization of the reported result (see lines 444, 448, 458, 479, 538, 601).

Mechanistic references: When describing pathways (e.g., epigenetic suppression of antigen presentation), explicitly indicate whether evidence is preclinical, translational correlative, or clinical.

Re: We thank the Reviewer for this important comment. In response, we systematically revised the manuscript to explicitly qualify the level of evidence supporting mechanistic statements. Throughout the text, we now clearly distinguish between preclinical, translational correlative, and clinical evidence when describing biological pathways, immune evasion mechanisms, and resistance processes. We also revised language to avoid implicit claims of clinical validation when evidence remains exploratory or hypothesis-generating. These changes improve conceptual clarity, methodological rigor, and interpretability of mechanistic insights in the context of available clinical data (see lines 196, 209, 229, 285, 294, 303, 351, 359, 405, 716, 727, 733, 740, 845).

Re: We thank the Reviewer for all the constructive comments. In response, we revised the manuscript to strengthen critical appraisal, standardize trial reporting, and improve clinical interpretability across therapeutic classes, while also refining language and presentation. We believe these changes have substantially improved the rigor and clarity of the Review.

Reviewer 2 Report

Comments and Suggestions for Authors

In general, the manuscript is well-organized and the information provided by the authors are interesting and timely. The topic selected for critical reviewing the recent development against immunotherapy resistance in small-cell lung cancer is important and would be impactful to the readers in the field. There are some suggestions given for the authors to revise the manuscript.

A brief description for the criteria to select the prior arts for critical review should be given.
The permission of using figure/picture needs to be clarified. Proper citation is needed in the figure legend.
For section 3, in each subsection focusing on the strategies development, the authors should concisely discuss the advantages and limitations of each strategy reviewed.
Section 4, discussion. This section is weak. The authors should refer to section 3 and think thoroughly how to address the limitations found in section 3. Then, propose possible/potential approaches/directions for readers/peers in the field to address such challenges ahead. This section has to be intensively revised with more input and efforts to make the manuscript be sound and impactful.
It appears that no clinical drugs for immunotherapy in small-cell lung cancer have been described. Which ones have shown resistance? It is preferred to make table to show these information.
Minor issues

- Table heading placing in top of the table with a bit detailed description.

- The first column, “Author”, could be located at the last column and changed to be “Reference”.

- The order of the table of contents can be arranged chronologically, based on the year of publication.

Author Response

Reviewer 2

A brief description for the criteria to select the prior arts for critical review should be given.

Re: We thank the reviewer for this suggestion. We included a subsection (1.1 Scope and approach) in which we better clarified the scope of our Review (following another Reviewer suggestion), and in this subsection we included a brief description of the selection criteria for the studies and evidence considered in this review, clarifying the focus on clinical trials, early-phase studies, and translational research in SCLC (lines 135-139).

The permission of using figure/picture needs to be clarified. Proper citation is needed in the figure legend.

Re: We thank the Reviewer for the comment. We have highlighted this point to the Editor-in-Chief, as copyright of our manuscript stands to the Editorial Office of the Journal. We guarantee that all Figures have been generated de novo basing on the focus of our manuscript.

For section 3, in each subsection focusing on the strategies development, the authors should concisely discuss the advantages and limitations of each strategy reviewed.

Re: We thank the Reviewer for the insightful comment. For each strategy we discussed along the text, we added a subparagraph “Clinical positioning and therapeutic sequencing considerations, key uncertainties”) in which we discuss advantages and disadvantages of each strategy, also proposing a possible clinical positioning basing on clinical significance (see paragrahs 3.1.1, 3.2.1, 3.3.1, 3.4.1, 3.5.1, 3.6.1).

Section 4, discussion. This section is weak. The authors should refer to section 3 and think thoroughly how to address the limitations found in section 3. Then, propose possible/potential approaches/directions for readers/peers in the field to address such challenges ahead. This section has to be intensively revised with more input and efforts to make the manuscript be sound and impactful

Re: We thank the Reviewer for the comment. We revised the entire Discussion to strengthen the critical appraisal, and to better connect section 4 with what discussed in section 3 (see Discussion).

It appears that no clinical drugs for immunotherapy in small-cell lung cancer have been described. Which ones have shown resistance? It is preferred to make table to show these information.

Re: We thank the Reviewer for the comment. To address this concern, we re-thought all tables, making slighter primary and secondary endpoints, to highlight which are the resistance and the responses to each strategy, as well as the objective response rates; moreover, the key therapeutic strategy have been highlighted to directly link it to patient responses.

Minor issues

Table heading placing in top of the table with a bit detailed description.

Re: We thank the Reviewer for the comment. We added clear table explication in Table heading, also resuming tables abbreviations.

The first column, “Author”, could be located at the last column and changed to be “Reference”.

Re: We thank the Reviewer for the comment. We accordingly modified the column “Author” to be the last, as “Reference”, for each table.

The order of the table of contents can be arranged chronologically, based on the year of publication.

Re: We thank the Reviewer for the comment. We kindly would note that the contents in the tables are already placed in chronological order, based on the year of publication; it is the exact way in which we intended to build the tables. In case the Reviewer meant another matter, we are completely available to read further comments.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript presents a comprehensive and timely review of strategies aimed at overcoming the limitations of immunotherapy in small cell lung cancer (SCLC), drawing on evidence from both published and ongoing clinical trials. The authors discuss a range of therapeutic approaches, including antibody–drug conjugates, bispecific antibodies, adoptive cell therapies, and combination strategies. The manuscript is well organized and informative. In particular, the detailed synthesis of studies employing diverse approaches to address immunotherapy resistance is valuable and provides helpful guidance for future research.

However, several minor issues should be addressed before acceptance:

Missing reference: A supporting reference should be cited for the statements in lines 309–313.
Abbreviations: All abbreviations should be defined in full at their first appearance (e.g., line 285, ADC).
Tables 1-4: To avoid confusion, the year of each study should be clearly stated in the format “20xx” rather than “Nov 23” which would be confused with a specific date.
Future directions: Expanding the discussion section to include a section on future directions would strengthen the manuscript by highlighting some key research priorities in the field.
Critical analysis: While the summary of different strategies is thorough, the manuscript would benefit from more critical discussion and comparison, such as the limitations of each approach and the unmet needs between preclinical research and clinical practice.

Author Response

Reviewer 3

However, several minor issues should be addressed before acceptance:

Missing reference: A supporting reference should be cited for the statements in lines 309–313.

Re: We thank the Reviewer for the comment. We added a reference for the cited lines (Phase II study of PM8002 plus paclitaxel in relapsed SCLC, data presented at ESMO Congress 2023, lines 546-547).

Abbreviations: All abbreviations should be defined in full at their first appearance (e.g., line 285, ADC).

Tables 1-4: To avoid confusion, the year of each study should be clearly stated in the format “20xx” rather than “Nov 23” which would be confused with a specific date.

Re: We thank the Reviewer for the comment. According to another Reviewer’s comment, we deleted the column “Author” with the year of publication, to move it as last column “Reference”.

We thank anyway the Reviewer for noticing the errors in the reporting of the dates.

Future directions: Expanding the discussion section to include a section on future directions would strengthen the manuscript by highlighting some key research priorities in the field.

Re: We thank the Reviewer for the comment. We strongly agree with the Reviewer that our manuscript lacks a clinical and critical vision for future directions; to address this concern, we added a new subparagraph at the end of the Discussion section (see 4.1 Future directions).

Critical analysis: While the summary of different strategies is thorough, the manuscript would benefit from more critical discussion and comparison, such as the limitations of each approach and the unmet needs between preclinical research and clinical practice.

Re: We really thank the Reviewer for the comment. We agree that our manuscript lacks a critical appraisal and of differentiating preclinical, exploratory and clinical evidence. To address this concern, for each therapeutic strategy, we added a comment for safety-driven study limitations (“Toxicity and feasibility consideration”), and a subparagraph “Clinical positioning and therapeutic considerations”, in which we discuss therapy sequencing, positioning and clinical potential of each approach, as well as the current evidences supporting them Moreover, for each study, we added the key limitations in the manuscript Tables.(see (3.1.1, 3.2.1, 3.3.1, 3.4.1, 3.5.1, 3.6.1, Tables 2, 3,4, 5).

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

It can be accepted

Comments on the Quality of English Language

There are some typos and grammatical problems.

Reviewer 2 Report

Comments and Suggestions for Authors

The revised manuscript seems improved with the newly added information and looks much better now.

Some minor points to be addressed before it could be ready for publication.

The heading of section 4.1 should be deleted. The new paragraph cold start with a sentence to state the contents about "Future directions".
Double check the typo errors and some repeated ".".