Hapten-Based Cancer Immunotherapy: From Immune Activation to Antitumor Activity

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The draft addresses a relevant subject with considerable potential; yet, it necessitates multiple precise modifications to improve conceptual clarity, analytical rigour, readability, and presentation quality.

1. Improve the clinical discussion by being more critical. The current clinical portion is informative, but it just describes things. It is prudent to delineate the principal limitations of the reported trials with greater clarity, encompassing small sample size, inadequacies in research methodology, and the difficulty of clearly connecting therapeutic benefit to haptenation.

2. Please change Table 1 so that it is clearer and more consistent.Table 1 is now hard to understand and seems to have entries that are either unnecessary or unclear. It would be helpful to reorganise the table, get rid of any duplicates, and make sure that the models, treatments, and outcomes are all properly and consistently explained.

3. Please explain the process of haptenation in more detail.In many parts of the article, it is not always clear what the difference is between creating new antigenic sites and boosting the immune response. An explanation of this sequence would make science more accurate and help readers understand how it works.

4. Please improve the phrasing and terminology throughout the manuscript.Some phrases are too long and hard to understand, and there are also some problems with grammar and terminology. Careful grammatical polish would make the review easier to read and better overall.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive overview of hapten-based cancer immunotherapies, tracing the concept from historical foundations to modern immunological mechanisms and clinical applications. The authors detail how haptenation alters antigen processing, enhances dendritic cell maturation, and drives both cellular and humoral antitumor responses. It is a timely and well-organized review that synthesizes a niche but growing area of immuno-oncology.

Major comments

The main issue is that several statements are stronger, broader, or more specific than the cited sources justify. The review would benefit from a clearer distinction between peer-reviewed mechanistic evidence, conference abstracts, clinical associations, and forward-looking interpretations.

• The STC-1010 translational section should be revised with greater caution. The manuscript presents the ex vivo human data with substantial mechanistic detail, including antigen uptake, dendritic cell maturation, clonal CD8 T cell expansion, HLA-dependent killing, and reproducibility across batches. However, Ref. 39 is a conference abstract rather than a full peer-reviewed publication. It is therefore difficult to verify the level of detail and certainty presented. Please explicitly label this evidence as preliminary and reduce the strength of the associated conclusions.
• The safety language is overstated in several places. For example, the manuscript states that preclinical and clinical evidence show these therapies are “well tolerated with no local or systemic toxicity.” This is too strong and is not consistent with Table 2, which reports mostly mild local reactions for M-Vax and mild treatment-related events in glioblastoma studies, rather than a complete absence of toxicity. Please revise this wording to more accurately reflect the data.
• The manuscript states that in resected stage III melanoma, the 5-year overall survival was “about 50%.” However, the cited 2004 JCO study reports an overall 5-year survival of 44% in that cohort. The current wording oversimplifies the result and should be corrected.
• On page 5, the manuscript states that coating tumor cells with DNP enables recognition by hapten-specific antibodies, leading to Fc receptor-mediated uptake by dendritic cells and enhanced T cell-mediated antitumor responses in mice, citing Ref. 24. However, Ref. 24 focuses on DNFB-induced MAPK activation and CD40 upregulation in skin-derived dendritic cells and does not appear to directly support this specific mechanism. Please provide a more appropriate citation or revise the statement.
• The “Challenges and Future Directions” section contains at least one reference assignment issue. The sentence describing complementary delivery systems cites nanoparticles [54,55], liposomes [56], and autologous coagulum platforms [57]. While Ref. 54 is indeed a nanoparticle vaccine delivery review, Ref. 55 relates to penicillin hapten-enhanced intratumoral chemotherapy, and Ref. 57 describes hapten-decorated DNA nanostructures rather than an autologous coagulum platform. These references appear misassigned and should be corrected.
• The conflict of interest disclosure indicates that several authors are employees of Brenus Pharma, the company developing the STC-1010 platform discussed in the manuscript. Although this is appropriately disclosed, Sections 4.1 and 4.2 place substantial emphasis on STC-1010. To maintain the balance expected in a review article, please either give comparable attention to alternative platforms or clearly state the scope and focus of the review. It would also be helpful to categorize cited studies as peer-reviewed preclinical studies, peer-reviewed clinical studies, conference abstracts, and ongoing or unpublished trials.
• I recommend a systematic verification that all statements in Tables 1 and 2 are directly supported by their cited references. This is particularly important for clinically relevant claims, as readers will treat these tables as authoritative summaries.

Minor comments

• There are multiple typographical and grammatical errors that should be corrected throughout the manuscript. Examples include:
  • “Conal T cells expansion” should be “clonal T cell expansion.”
  • In the legend for Table 2, there are duplicated semicolons, for example: “DNP:Dinitrophenyl;;; DTH:Delayed-Type Hypersensitivity;; HR:Hazard ratio;”
  • “discease stabilization” should be “disease stabilization.”
    Please carefully proofread the entire manuscript.
• ADCC and CDC are defined in the main text but should also be explicitly spelled out in the Figure 1 legend, if space allows.
• The abbreviation “DTH” (Delayed-Type Hypersensitivity) is defined multiple times throughout the manuscript. It should be defined once and used consistently thereafter.

Author Response

Please see the attachment

Author Response File: Author Response.pdf