Tumor necrosis factor receptor superfamily costimulatory domains (TNFRSF-ICDs)

Tumor necrosis factor receptor (TNFR)-derived intracellular signaling domains are modular protein components used to engineer synthetic receptors, primarily second and third-generation Chimeric Antigen Receptors (CARs) (Source: Nature Reviews Drug Discovery, 2015). These domains are typically sourced from the Tumor Necrosis Factor Receptor Superfamily (TNFRSF), with 4-1BB (TNFRSF9), OX40 (TNFRSF4), and CD27 being the most common examples utilized in clinical applications (Source: UniProt P41273). Their primary biological function is to provide costimulatory signals that complement primary T-cell receptor signaling, leading to robust activation, proliferation, and cytokine production (Source: PubMed: 15123770). In CAR-T therapy, TNFR-derived domains like 4-1BB are often preferred for their ability to enhance mitochondrial biogenesis and promote a memory-like T-cell phenotype, which significantly improves the persistence of the therapeutic cells in vivo compared to CD28-based designs (Source: Nature Medicine, 2015). Clinically, these domains are foundational to several FDA-approved CAR-T products, such as Tisagenlecleucel and Lisocabtagene maraleucel, used to treat hematologic malignancies (Source: FDA Labels). Beyond synthetic engineering, the parent receptors are also targets for agonistic monoclonal antibodies designed to stimulate endogenous anti-tumor immunity. However, their use is associated with specific safety concerns, including cytokine release syndrome and potential neurotoxicity, which require careful management during therapy.

Other names

Tumor necrosis factor receptor-derived intracellular signaling domainsTNFRSF signaling domains4-1BB signaling domainOX40 signaling domainCD27 signaling domainCD137 signaling domainCostimulatory signaling elements

These domains function as costimulatory signaling modules that, upon activation, recruit Tumor Necrosis Factor Receptor-Associated Factors (TRAFs) to the cytoplasmic tail of the receptor. This recruitment triggers downstream signaling cascades, including the canonical and non-canonical NF-kappaB pathways, the PI3K/Akt pathway, and the MAPK/ERK pathway, which collectively promote T-cell survival, cytokine production, and metabolic fitness (Source: Nature Reviews Drug Discovery, 2015; UniProt P41273).