Tumor necrosis factor receptor superfamily member 9 (4-1BB) co-stimulatory domain (4-1BB)

The 4-1BB co-stimulatory domain is a signaling component derived from the intracellular portion of the Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9), also known as CD137 (UniProt P41273). In Chimeric Antigen Receptor (CAR) T-cell therapy, this domain is integrated into the synthetic receptor to provide essential secondary activation signals upon antigen binding. Unlike the CD28 domain which favors rapid glycolytic metabolism and effector differentiation, the 4-1BB domain promotes oxidative phosphorylation and the development of memory T-cells, leading to enhanced persistence of the therapeutic cells in the patient's body (Kawalekar et al., 2016, PubMed: 26898879). The signaling mechanism involves the recruitment of Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), which subsequently activate the NF-kappaB and JNK pathways to support cell survival and proliferation (PubMed: 26121087). This domain is a key feature of several FDA-approved CAR-T therapies, including Tisagenlecleucel (Kymriah) and Lisocabtagene maraleucel (Breyanzi), which are used to treat hematologic malignancies like B-cell lymphoma and leukemia (FDA, 2017). By reducing T-cell exhaustion and maintaining a durable anti-tumor response, the 4-1BB domain has become a cornerstone in the design of second-generation CARs (Long et al., 2015, PubMed: 25939063). Its inclusion is particularly beneficial for targets where tonic signaling might otherwise lead to premature T-cell dysfunction.

Other names

CD137TNFRSF9Induced by lymphocyte activationILA4-1BB intracellular signaling domain4-1BB ICD

Provides co-stimulatory signaling (Signal 2) through the recruitment of TRAF1 and TRAF2 adapter proteins, which activates NF-kappaB and MAPK pathways to enhance T-cell persistence and metabolic fitness.