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

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), commonly known as 4-1BB or CD137, is a potent costimulatory receptor expressed primarily on activated T cells and natural killer (NK) cells (UniProt P41273). Upon binding to its ligand (4-1BBL) or an agonistic antibody, it triggers signaling pathways such as NF-κB and MAPK, which promote T-cell proliferation, survival, and cytokine production (PubMed: 28137874). In the context of oncology, 4-1BB is a critical target for cancer immunotherapy because its activation enhances the anti-tumor activity of cytotoxic T lymphocytes and prevents exhaustion. Several agonistic monoclonal antibodies, such as urelumab and utomilumab, have been developed to exploit this pathway, though clinical progress has been tempered by dose-limiting hepatotoxicity observed with early candidates (ClinicalTrials.gov: NCT00309010). Beyond monoclonal antibodies, the 4-1BB intracellular signaling domain is a standard component of second-generation chimeric antigen receptor (CAR) T-cell therapies, such as tisagenlecleucel, to improve persistence and metabolic fitness. Current research focuses on developing next-generation agonists with better safety profiles, such as bispecific antibodies that require tumor-localized cross-linking to activate the receptor.

Other names

CD137ILAInduced by lymphocyte activationTNFRSF94-1BB receptor

Agonism of the receptor to enhance T-cell and NK cell mediated anti-tumor immunity; also used as a costimulatory domain in CAR-T cell constructs to improve persistence.