Novel Immunotherapeutic Strategies for Castration-Resistant Prostate Cancer: Mechanisms and Clinical Advances

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript “Novel Immunotherapeutic Strategies for Castration-Resistant Prostate Cancer: Mechanisms and Clinical Advances” is a timely narrative review that synthesizes key 2020–2025 advances in CRPC immunotherapy, spanning vaccine approaches, immune checkpoint inhibitors (ICIs), combination regimens, and emerging targeted agents. It highlights notable signals such as the Xaluritamig bispecific antibody achieving a 59% PSA50 response and P-PSMA-101 CAR-T showing >50% PSA decline, while clearly outlining major resistance pathways including the AR-LLT1 axis, Pygo2-mediated immunosuppression, and HnRNP L–driven splicing effects. The discussion extends to innovative delivery platforms (e.g., CM-AMS@AD multifunctional nanoparticles) that may enhance T-cell infiltration and antitumor activity. Trial summary tables and BioRender figures improve accessibility and reference utility. Overall, the review aligns well with Current Issues in Molecular Biology (CIMB) by bridging translational mechanisms with clinical outcomes, and its structured compilation of ~4 vaccine, ~5 ICI, ~18 combination, and ~6 targeted trials provides a valuable centralized resource for the field. 

However, revisions are required to improve rigor, interpretability, and presentation quality.  

First, most sections list trial outcomes without sufficient interpretation. The manuscript does not analyze reasons for failure, compare therapeutic strategies, or discuss clinical significance and toxicity trade-offs. Consequently, the review remains descriptive rather than integrative and lacks clear identification of the most promising approaches or implications for future development. 

Second, the review is not reproducible because the literature selection methodology is inadequately described. Search terms, date limits, additional databases, and explicit inclusion/exclusion criteria are missing. A concise Search Strategy is strongly recommended. 

Minor issues: 

1. Line 33: Replace “robustly demonstrate” with “suggest potential but require validation in larger trials.”
2. The novelty statement should be refined to clearly articulate how this review differs from and adds to the existing literature.
3. The Abstract contains redundant statements regarding the promise of immunotherapy.
4. For several trials, key information such as sample size, study design, and patient population is missing, which limits interpretation of the reported efficacy.
5. Professional English editing is recommended to correct hyphenation inconsistencies (e.g., “check-point,” “an-ti-tumor,” “pep-tide-based”) and eliminate redundant language. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Major Scientific Comments

1. Contextualizing "Cold" Tumor Dynamics

Observation: The authors correctly identify prostate cancer as an immunologically "cold" tumor with low mutational burden and sparse T-cell infiltration.

Recommendation: To strengthen the "Mechanisms" portion of the title, the authors should deeper explore why current ICIs fail beyond just "cold" status. Specifically, discussing the role of the prostatic acid phosphatase (PAP) or the impact of the dense stroma in physical immune exclusion would add significant mechanistic value.

2. Clarification of PSA Response vs. Survival Benefits

Observation: The manuscript highlights several "promising" results based on PSA50 responses, such as Xaluritamig (59%) and P-PSMA-101 (>50%).

Comment: As noted in the discussion of Sipuleucel-T, overall survival (OS) can improve even without significant PSA declines. The authors should explicitly caution that in CRPC, PSA response is a surrogate marker and does not always correlate with OS, particularly in immunotherapy where "pseudo-progression" can occur.

3. Integration of Myeloid-Derived Suppressor Cells (MDSCs)

Observation: The basic research section identifies G-MDSCs as critical targets, noting that IFNα can reduce their immunosuppressive function.

Comment: Given that MDSCs are a primary driver of the "cold" microenvironment in CRPC, this section is a highlight of the paper. However, it would be beneficial to link these preclinical G-MDSC findings back to the failed ICI trials mentioned in Table 2 to explain why monotherapy is insufficient.

4. Refinement of Nanotechnology Discussion

Observation: The paper discusses the CM-AMS@AD nanoparticle, which integrates photothermal, chemo, and immunotherapy.

Recommendation: While the preclinical results are robust, the authors should address the translational challenges of "triple-combination" nanoparticles, such as large-scale manufacturing consistency (CMC) and potential cumulative toxicity that may not be evident in mouse models.

Minor Points and Technical Corrections

Surrogate Endpoint Clarification: On page 3, line 112, the text defines "PSA" as "Progression-Free Survival". This is a typo; PSA refers to Prostate-Specific Antigen. The acronym for Progression-Free Survival is PFS.

Table Consistency: In Table 3, several trials (e.g., NCT03016312) are listed as "Stopped early". The authors should briefly state the specific safety signal or lack of efficacy that led to early termination to better inform the reader of the risks in combination therapy.

Figure Citations: Ensure Figure 1 (A, B, C) is clearly cross-referenced in the text when discussing the specific mechanisms of LLT1, HnRNP L, and Pygo2 to improve the flow for the reader.

  Comments on the Quality of English Language

Grammatical Errors and Phrasing

• Sentence Fragments: Some sentences are incomplete or lack proper verbs. For example, "While standard androgen-deprivation therapy (ADT)... demonstrate initial clinical benefit..." should be integrated into a single cohesive sentence.

   

  Subject-Verb Agreement: There are minor errors in agreement, such as "Currently, there have been studied that have found...". This should be corrected to "Currently, studies have found..." or "It has been found in recent studies...".

   

  Awkward Syntax: The sentence "Ultimately, this comprehensive analysis serves clarifying the current state..." is missing the preposition "to" (i.e., "...serves to clarify...").

  3. Punctuation and Formatting

  Citation Formatting: In the abstract and introduction, citations are sometimes attached to the middle of words or phrases without spaces (e.g., "inhibitors (ICIS)11" and "mechanisms3. 4").

  Numerical Notation: The use of symbols like "$I/\Pi$" or "$I/2$" to represent trial phases (Phase I/II or Phase 1/2) is non-standard for medical literature and should be replaced with standard Roman or Arabic numerals.

  Table Clarity: Some table entries contain broken words or unusual hyphenation (e.g., "replica-tion-in-vi-competent" and "chim-panzee"), which likely occurred during the PDF conversion but should be corrected for the final manuscrip

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Prostate cancer often progresses to lethal, drug- and castration-resistant prostate cancer. Conventional therapies often fail due to various resistance mechanisms. Because of the resistance patients are left with limited options and poor prognoses. Immunotherapy is a promissing strategy to overcome the drug resistance challenge in castration-resistamt prostate cancer. The review by Xia and co-workers synthesizes findings from PubMed literature in the period from 2020 to 2025. Clinical trial progress in the period 2020-2025 revealed significant progress in the area of vaccinotherapy, immunotherapy with checkpoint inhibitors and combined therapies (Section 2). Basic research identified 4 targeted resistance mechanisms and 1 nanoparticle-mediated triple-combination therapy, which enhanced cytotoxic T-cell infiltration and suppressed the cancer growth pre-clinically (section 3). These findings demonstrate the therapeutic promise of immunotherapy of the cancer in overcoming resistance barriers and improving patients outcomes. However, translating this potential into clinical practice requires optimized patient selection through predicitive biomarkers and rigorously validated phase III trials.

This is an interesting review article that can be accepted after a minor revision. Two points should be addressed:

1) The main problem with this article is text similarity higher than 20%, which is higher than the "healthy" level of 10%. The text needs to be re-written in order to reduce the text similarity level to the "healthy" range (<10%). 

2) The article should be supplied with a short summary and/or with a graphical abstract. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I appreciate the authors’ careful and thorough revisions. They have thoughtfully addressed all of my previous concerns. The addition of deeper mechanistic insights, comparative perspectives, and a clearly described search strategy has substantially strengthened the manuscript and turned it into a useful, centralized reference for the CRPC immunotherapy field. I have no further comments and support its publication.