IL-18-Mediated Tumor Immune Evasion

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review manuscript provides a timely and comprehensive synthesis of the dual and context-dependent roles of interleukin-18 (IL-18) in tumor immune evasion. The topic is highly relevant to the fields of cancer immunology and immunotherapy, aligning well with the journal's scope and the special issue on targeted cancer therapy. The authors have undertaken a thorough literature review, presenting a detailed, well-organized, and mostly up-to-date summary of IL-18's biology, its interaction with IL-18BP, signaling mechanisms, and its complex involvement in shaping the tumor microenvironment. The manuscript is clearly written and structured.

 

1. The manuscript describes "what" is known about IL-18 but falls short on the "so what" and "what next." A high-impact review should not only summarize but also integrate, critique, and propose. I recommend the authors restructure the conclusion (Section 5) to provide a powerful, unifying model or hypothesis. For instance, they could propose a "Threshold and Context Model" for IL-18, graphically illustrating how concentrations, receptor expression, co-existing cytokines (IL-12, IL-2, etc.), and specific TME components (dominant immune cell types, level of IL-18BP) collectively determine whether IL-18 acts as an immunostimulant or an immunosuppressant in different cancers. This would synthesize the existing data into a predictive framework.
2. The text rightly points out the dual roles of IL-18 but treats contradictions descriptively. For example, the statement about IL-18 having opposing effects in gliomas versus colon cancer (Page 8) is crucial but not dissected. The authors should dedicate a subsection (e.g., within Section 3 or 5) to critically analyze these disparities. They should hypothesize potential explanations: Are differences due to tissue-specific stromal interactions, unique metabolic features of these cancers, or distinct patterns of IL-18BP expression and regulation? Engaging deeply with these controversies would be a major strength.
3. Section 4 lists therapeutic strategies but lacks a critical assessment of their translational feasibility and challenges. The discussion on side effects is superficial ("should be briefly discussed," Page 9). The authors should provide a balanced and detailed analysis of the risks associated with systemic IL-18 modulation (e.g., exacerbation of autoimmunity, cytokine storm, impact on non-tumor immunity) versus the promises of localized delivery (e.g., engineered CAR-T cells). A table comparing different modalities (antibodies, gene therapy, combination therapies) with their mechanisms, development stage, and key challenges would be highly valuable.
4. The discussion on AI and precision medicine reads as speculative and generic. Without concrete examples of AI models applied to IL-18 data or specific "biomarkers" identified by machine learning, this section feels out of place. I recommend either substantially strengthening this part with citations to pioneering studies in computational immunology or condensing it to a brief, focused outlook on the potential of systems biology approaches to decipher IL-18 networks.
5. Figure 1 is too generic and does not add value specific to IL-18. Figure 3's title ("Mechanism diagram of IL-18 acting on Toll-like receptors") is confusing, as IL-18 signaling is not primarily mediated through TLRs. These figures should be replaced or significantly revised to directly illustrate the core concepts of the review (e.g., the proposed conceptual model, the IL-18/IL-18BP axis in the TME, or a detailed signaling map integrating immune evasion outcomes).
6. Table 1 is a good idea but poorly executed. The column "Clinical treatment strategies" lists approaches that are mostly experimental (e.g., "Attempt to arm CAR-T..."), not established clinical strategies. The table should be reframed to summarize "Observed Clinical Correlations and Experimental Therapeutic Directions" to avoid misleading readers about the clinical readiness of these interventions.
7. the sentence "The expression level of IL-18 was lower in well-differentiated tumor tissues and almost not expressed in poorly differentiated tumors" is a key observation. Please clarify if this is specific to brain tumors or a general phenomenon, and discuss its potential implication for immune evasion.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Overall assessment

This manuscript provides a comprehensive and timely review of the pleiotropic roles of IL-18 in tumor immune evasion, with particular emphasis on immune cell regulation, tumor-intrinsic effects, and therapeutic targeting strategies. The authors have assembled an extensive body of literature and present a structured overview that will be useful for investigators entering the IL-18 field.

That said, in its current form the manuscript is overly descriptive, occasionally mechanistically imprecise, and lacks sufficient critical synthesis expected for a high-impact review. Several sections blur correlation and causation, and important conceptual distinctions (e.g., IL-18 concentration, cellular source, IL-18BP dominance, and spatial context within the TME) are not consistently enforced. Language and clarity issues are also frequent.

With major revision, this manuscript could become a valuable reference.

Major comments

1. Conceptual framing: IL-18 as a “contextual rheostat” rather than a dual-role cytokine

The manuscript repeatedly states that IL-18 has “dual roles” (pro-tumor vs anti-tumor). While factually correct, this framing is now outdated and oversimplified.

Concerns

• The review does not clearly define what determines directionality (cellular source, IL-18:IL-18BP ratio, receptor density, chronic vs acute exposure).
• Statements such as “low concentration anti-tumor, high concentration pro-tumor” are asserted but not mechanistically justified and risk oversimplification.

2. Overstatement of mechanistic certainty (correlation vs causation)

Several sections imply direct causality where only associative or context-limited data exist.

Examples:

• IL-18 > PD-L1 induction is presented as a general mechanism, but this is tumor-type-specific and often indirect (via STAT3, IFN-gamma loops, or NF-kB).
• IL-18-induced T cell exhaustion is described as linear and deterministic, whereas published data (e.g., pancreatic vs melanoma models) show divergent outcomes.

3. IL-18BP is under-theorized relative to its importance

Although IL-18BP is frequently mentioned, it is treated largely as a passive antagonist rather than an active immune checkpoint.

Concerns

• No dedicated section synthesizes IL-18BP biology across tumor types.
• The emerging concept of IL-18BP dominance over IL-18 signaling (including decoy-resistant IL-18 variants) is underdeveloped.

4. CAR-T / engineered cell therapy section lacks immunotoxicity depth

The CAR-T section is timely but overly focused on efficacy, with insufficient discussion of translational risks.

Concerns

• IL-18-secreting CAR-T cells are discussed largely positively.
• CRS, neurotoxicity, macrophage activation syndrome, and NK-cell hyperactivation are only superficially addressed.

5. Figures and tables: informative but not integrative

• Figures 2 and 3 largely recapitulate textbook signaling pathways.
• Table 1 mixes preclinical rationale with speculative “clinical strategies” without hierarchy of evidence.
• The fonts in all the figures have to be standardized and ensure there’s an alignment between borders/

Minor comments

1. Language and grammar
• Numerous typographical and grammatical errors (“complication” → “complexity,” inconsistent pluralization, awkward sentence construction).
2. Redundancy
• IL-18 signaling via MyD88/NF-κB is repeated multiple times with minimal new insight.
• Consolidate signaling descriptions into one core section.
3. Terminology
• Clarify inconsistent use of “immune evasion,” “immune suppression,” and “immune tolerance.”
• Distinguish NK cell dysfunction from T cell exhaustion more clearly.

Comments on the Quality of English Language

Strongly recommend professional English editing.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is now suitable for acceptance. The authors have diligently addressed all the reviewers' concerns through substantive and satisfactory revisions. The newly introduced conceptual model, the critical mechanistic analysis, the enhanced assessment of therapeutic strategies, and the refined figures collectively elevate the manuscript's scholarly impact and clarity to meet the journal's standards.

Author Response

We are grateful for your positive comment and approval of our revised manuscript. We sincerely thank you for your time and valuable guidance that greatly enhanced our manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

No further comments. The authors have addressed most of the comments.

Author Response

We are grateful for your positive comment and approval of our revised manuscript. We sincerely thank you for your time and valuable guidance that greatly enhanced our manuscript.