TNFSF18 (tumor necrosis factor superfamily member 18), also known as glucocorticoid-induced TNFR-related protein ligand (GITRL), is a type II transmembrane protein belonging to the TNF superfamily. It interacts with its receptor GITR (TNFRSF18), primarily expressed on regulatory T cells (Tregs) and activated conventional T cells. This ligand-receptor axis plays a critical role in modulating immune responses by balancing T cell activation and suppression. TNFSF18 is constitutively expressed on antigen-presenting cells (e.g., dendritic cells, macrophages) and endothelial cells, while its expression can be induced in other cell types during inflammation.
TNFSF18 antibodies, either agonistic or antagonistic, have emerged as therapeutic tools to manipulate immune regulation. Agonistic antibodies targeting GITR aim to enhance antitumor immunity by activating effector T cells and overcoming Treg-mediated immunosuppression in cancer. Conversely, blocking antibodies against TNFSF18/GITRL may suppress excessive inflammation in autoimmune diseases. Preclinical studies in murine models demonstrate that TNFSF18 pathway modulation influences autoimmune conditions like rheumatoid arthritis, colitis, and graft-versus-host disease. However, clinical translation remains challenging due to the dual role of GITR signaling in promoting both effector T cell function and Treg stability. Current research focuses on optimizing antibody specificity, timing, and combination therapies to minimize off-target effects and cytokine release syndromes. Several TNFSF18/GITR-targeting antibodies are under evaluation in early-phase clinical trials for cancer immunotherapy.