IL-18 receptor pathway (engineered IL-18 cytokine)

Class

Engineered interleukin-18 (IL-18) variant, immune-stimulatory cytokine

Pathway

Overcomes IL-18BP-mediated suppression to boost anti-tumor immune (NK/T-cell) activity

Interleukin-18 (IL-18) is a signaling protein of the interleukin-1 family that, under normal conditions, helps coordinate innate and adaptive immune responses by activating natural killer (NK) cells and certain T cells to produce interferon-gamma and enhance their tumor-killing activity. A major limitation of using natural IL-18 as a therapeutic is that the body produces a soluble decoy protein, IL-18 binding protein (IL-18BP), which binds IL-18 tightly and neutralizes it before it can engage its receptor. Many tumors exploit this by driving high local IL-18BP levels, effectively silencing endogenous IL-18 signaling in the tumor microenvironment. An engineered IL-18 variant is designed to retain the ability to activate the IL-18 receptor complex on immune cells while being structurally altered so that IL-18BP can no longer bind and sequester it. This allows the cytokine to remain active where tumors would otherwise suppress it, sustaining NK- and T-cell mediated anti-tumor activity. This mechanism is broadly relevant to cancer immunotherapy, particularly in settings where immune evasion occurs through cytokine neutralization rather than through the checkpoint pathways targeted by more established immunotherapies.