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Interleukin-18-binding protein (IL18BP) is a pivotal extracellular gatekeeper of IL-18 activity and an emerging therapeutic target in cancer. By sequestering mature IL-18, IL18BP controls the receptor-accessible free ligand within the tumor microenvironment. The consequences are highly context dependent: IL18BP may suppress beneficial natural killer- and T-cell responses, yet also restrain IL-18-driven immune tolerance, inflammation, and metastatic adaptation. Here, we outline the mechanisms, cellular sources, tissue distribution, and cancer-specific roles of the IL-18/IL18BP axis. We emphasize that total, bound, and free IL-18 are biologically distinct and must be interpreted alongside IL18BP abundance, receptor competence, responder-cell identity, and treatment context. Accordingly, IL18BP blockade or decoy-resistant IL-18 agonists may restore antitumor immunity in selected settings, whereas preserving or enhancing IL-18 neutralization may be protective in others. Precision therapeutic tuning, rather than indiscriminate blockade, will be essential to translate this axis into effective biomarkers and cancer treatments.
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Huang et al. (2026) studied this question.
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