Tumor necrosis factor receptor superfamily co-stimulatory receptors (TNFRSF co-stimulatory receptors)

The Tumor necrosis factor receptor superfamily (TNFRSF) co-stimulatory receptors are a group of transmembrane proteins that provide essential secondary signals for the activation, expansion, and survival of T cells and Natural Killer (NK) cells [Buchan et al., 2018, Nature Reviews Drug Discovery]. Prominent members of this group include 4-1BB (CD137), OX40 (CD134), GITR (CD357), CD27, and CD40 [Ward-Kavanagh et al., 2016, Immunity]. These receptors typically function by binding to their respective ligands, which triggers the recruitment of TNF receptor-associated factors (TRAFs) to their cytoplasmic domains, initiating downstream signaling pathways like NF-κB and MAPK [Aggarwal, 2003, Nature Reviews Immunology]. In the context of oncology, these receptors are exploited as therapeutic targets to enhance the immune system's ability to recognize and destroy malignant cells. Agonistic monoclonal antibodies and multispecific biologicals are being developed to trigger these receptors, thereby boosting anti-tumor immunity [Chester et al., 2018, Blood]. However, the clinical application of these agents has been complicated by systemic toxicities, such as hepatotoxicity and cytokine release syndrome, leading to a shift toward more localized or conditional activation strategies [Sanmamed et al., 2015, Seminars in Oncology].

Other names

TNFRSF co-stimulatorsTumor necrosis factor receptor superfamily member 9 (4-1BB)Tumor necrosis factor receptor superfamily member 4 (OX40)Tumor necrosis factor receptor superfamily member 18 (GITR)Tumor necrosis factor receptor superfamily member 7 (CD27)Tumor necrosis factor receptor superfamily member 5 (CD40)Tumor necrosis factor receptor superfamily member 14 (HVEM)

Agonism of TNFRSF receptors to provide co-stimulatory signals that enhance T cell and NK cell activation, proliferation, and survival [Buchan et al., 2018, Nature Reviews Drug Discovery].