Tumor necrosis factor receptor superfamily member 9 (TNFRSF9) (CD137)

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), commonly known as CD137 or 4-1BB, is a potent costimulatory receptor expressed primarily on activated T cells, natural killer (NK) cells, and dendritic cells (UniProt: Q07011). It functions as a critical regulator of the immune response by promoting the survival, expansion, and metabolic fitness of CD8+ cytotoxic T lymphocytes through the activation of NF-kappaB and other pro-survival signaling pathways (PubMed: 28430541). In oncology, CD137 is a high-priority therapeutic target because its activation can overcome T-cell exhaustion and enhance the anti-tumor activity of the host immune system (NIH: PMC5553531). Beyond direct agonistic antibodies like urelumab and utomilumab, the cytoplasmic signaling domain of CD137 is frequently incorporated into second-generation chimeric antigen receptor (CAR) T-cell therapies, such as Tisagenlecleucel, to improve the persistence and long-term efficacy of the engineered cells (StatPearls: NBK557723). However, clinical development of systemic CD137 agonists has been complicated by significant safety concerns, most notably severe hepatotoxicity, leading to the current exploration of bispecific and tumor-localized delivery formats to maximize the therapeutic index (PubMed: 30898864).

Other names

4-1BBInduced by lymphocyte activationILAT-cell antigen 4-1BBT-cell antigen ILACDw137

Agonistic binding to CD137 triggers the recruitment of TNF receptor-associated factors (TRAF1 and TRAF2) to its cytoplasmic domain, leading to the activation of NF-kappaB, MAPK, and PI3K/Akt pathways that enhance T-cell survival, clonal expansion, and effector cytokine production.