Tumor necrosis factor receptor superfamily member 9 (TNFRSF9) intracellular domain (4-1BB ICD)

The 4-1BB intracellular co-stimulatory domain is a functional signaling component derived from the Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9), also known as CD137 [1]. Naturally expressed on activated T-cells and natural killer cells, this domain provides essential survival and proliferation signals upon binding its ligand, 4-1BBL [4]. The domain functions by recruiting Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), particularly TRAF1 and TRAF2, which initiate downstream signaling through the NF-kappaB and MAPK pathways [4, 5]. In modern immunotherapy, this domain is a critical element of second-generation Chimeric Antigen Receptor (CAR) T-cell therapies, such as Tisagenlecleucel and Lisocabtagene maraleucel [3]. When incorporated into a CAR construct, the 4-1BB domain enhances the metabolic fitness of T-cells by promoting mitochondrial biogenesis and oxidative phosphorylation [2]. This metabolic shift favors the development of central memory T-cells, leading to significantly longer persistence of the therapeutic cells in the patient's body compared to those using the CD28 domain [2, 5]. Clinically, the use of the 4-1BB domain is associated with sustained anti-tumor responses in hematologic malignancies like B-cell lymphomas and multiple myeloma [3]. However, the potent activation mediated by this domain can trigger severe side effects, most notably cytokine release syndrome (CRS) and neurotoxicity [3]. Ongoing research aims to fine-tune this signaling domain to maximize therapeutic efficacy while minimizing these systemic toxicities [5].

Other names

CD137 intracellular domainTNFRSF9 cytoplasmic domain4-1BB signaling domainILA (Induced by Lymphocyte Activation) cytoplasmic tail

Recruitment of TRAF1, TRAF2, and TRAF3 adapter proteins to activate NF-kappaB and MAPK signaling pathways, promoting T-cell persistence and memory differentiation [4, 5].