Interleukin-18 receptor complex (IL-18R) (IL-18R)

The Interleukin-18 receptor (IL-18R) complex is a heterodimeric signaling assembly composed of the ligand-binding IL-18Rα (IL18R1) and the signal-transducing IL-18Rβ (IL18RAP) subunits (UniProt Q13478, O95256). As a member of the Interleukin-1 receptor superfamily, it is expressed on various immune cells, including T cells and Natural Killer (NK) cells, where it mediates pro-inflammatory responses through the MyD88/IRAK/NF-κB signaling axis (Kaplanski, 2018). In the context of oncology, the IL-18 receptor complex on PD-1+ (exhausted) T cells has emerged as a critical target for immunotherapy. Research has demonstrated that while PD-1+ tumor-infiltrating lymphocytes are often dysfunctional, they maintain high expression of IL-18R, and signaling through this receptor can restore their effector functions and promote potent anti-tumor immunity (Zhou et al., 2020). Therapeutic strategies include the development of "decoy-resistant" IL-18 (DR-18) variants, such as ST-067, which are engineered to activate the receptor complex without being neutralized by the endogenous inhibitor IL-18 binding protein (IL-18BP) (Simcha Therapeutics, 2024). This approach aims to selectively enhance the activity of exhausted T cells within the tumor microenvironment, potentially synergizing with existing checkpoint inhibitors. Beyond cancer, the IL-18 receptor complex is also a target for inhibition in inflammatory and autoimmune diseases where IL-18 signaling is pathologically elevated. Clinical trials are currently evaluating the safety and efficacy of these novel IL-18 receptor agonists in patients with advanced solid tumors.

Other names

IL-18R1/IL-18RAP complexInterleukin-1 receptor-related proteinIL-1RrpIL-18 receptor alpha and beta complex

Agonism of the Interleukin-18 receptor complex to stimulate pro-inflammatory signaling and restore effector function in exhausted T cells.