Therapeutic engineering of the IL-18-IL-18BP axis for precision cancer immunotherapy.

Interleukin-18 (IL-18) is a pleiotropic cytokine that promotes interferon-γ (IFN-γ) production and cytotoxicity in natural killer (NK) and T cells, but its antitumor activity is limited by ligand maturation and release, IL-18-binding protein (IL-18BP) sequestration, IL-18 receptor (IL-18R) abundance and signaling competence, exposure kinetics, and the tumor microenvironment. This regulatory network may explain the limited and heterogeneous objective responses observed in early clinical studies of recombinant human IL-18 (rhIL-18). Here, we review strategies for engineering the IL-18-IL-18BP axis for cancer immunotherapy, including decoy-resistant IL-18 (DR-18) variants, IL-18R agonists and mimetics, oncolytic virus (OV)-mediated delivery, IL-18-armored adoptive cell therapies (ACT), membrane-tethered IL-18, and combinations with immune checkpoint blockade (ICB). Preclinical studies support intratumoral immune activation and tumor control, whereas early clinical studies of IL-18-armored cellular therapies highlight cytokine release syndrome (CRS), prolonged cytopenias, and systemic inflammation as major safety concerns. Accordingly, clinical development should evaluate target engagement, antitumor activity, and safety as distinct dimensions, integrating free and IL-18BP-bound IL-18, IL-18R expression, downstream signaling competence in effector cells, spatial immune contexture, and inflammatory toxicity. Conditional or tumor-restricted activation, controllable expression, and exposure profiles matched to tumor biology may be required to establish a clinically manageable therapeutic window for IL-18-based immunotherapy.