Tumor necrosis factor receptor superfamily member 9 (4-1BB) and Tumor necrosis factor receptor superfamily member 4 (OX40) (4-1BB/OX40)

4-1BB (CD137) and OX40 (CD134) are potent costimulatory receptors belonging to the tumor necrosis factor receptor superfamily (TNFRSF) that are upregulated on T cells following antigen-specific activation (UniProt P43489, Q07011). In the context of alloreactivity, such as graft-versus-host disease (GvHD), these receptors serve as specific markers for host-reactive T cells that drive tissue damage and organ rejection (Croft, 2010). Therapeutic strategies targeting these molecules include agonistic antibodies to boost anti-tumor immunity in oncology and antagonistic or depleting agents to suppress alloreactive responses in transplantation (Chester et al., 2018). 4-1BB signaling primarily enhances CD8+ T cell survival and metabolic fitness, while OX40 supports both CD4+ and CD8+ T cell expansion and inhibits regulatory T cell function. Clinical development has been complicated by safety issues, most notably the dose-limiting hepatotoxicity observed with systemic 4-1BB agonists like urelumab (NCT01471210). Consequently, current research focuses on bispecific antibodies and localized delivery systems to improve the therapeutic index of targeting these pathways. This entry is marked as incorrect because it combines two distinct molecular targets (TNFRSF9 and TNFRSF4) into a single descriptive category.

Other names

CD137TNFRSF9ILA (Induced by Lymphocyte Activation)CD134TNFRSF4ACT35TXGP1L

Agonism of TNFRSF4 and TNFRSF9 to enhance T-cell costimulation, proliferation, and survival; or targeted depletion/antagonism of activated alloreactive T cells expressing these markers.