Tumor necrosis factor receptor superfamily member 9 (4-1BB) intracellular costimulatory domain in Antibody-Coupled T-cell Receptor (ACTR) (4-1BB ICD in ACTR)

The 4-1BB intracellular costimulatory domain is a signaling component derived from Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9), utilized within the Antibody-Coupled T-cell Receptor (ACTR) platform (UniProt Q07011). ACTR is a universal chimeric receptor that pairs an extracellular CD16 (FcγRIIIa) domain with intracellular signaling motifs, including 4-1BB and CD3-zeta, to enable T-cell activation via co-administered monoclonal antibodies (Kudo et al., 2014, Cancer Research). When the ACTR-T cell binds to the Fc region of a tumor-bound antibody, the 4-1BB domain recruits TNFR-associated factors (TRAFs) to trigger NF-κB and MAPK signaling pathways (PubMed: 24737101). This costimulatory signal is crucial for enhancing T-cell metabolic fitness, promoting long-term persistence, and preventing exhaustion in the tumor microenvironment (Shirasu et al., 2017, Anticancer Research). Clinically, this domain has been evaluated in constructs like ACTR087 for B-cell malignancies, where it serves to amplify the cytotoxic response initiated by primary TCR-like signaling (Cogent Biosciences).

Other names

CD137 intracellular domainTNFRSF9 signaling domainACTR costimulatory domain4-1BB signaling domain

The 4-1BB intracellular domain provides costimulatory signals upon receptor clustering, recruiting TRAF adapter proteins to activate NF-kappaB and MAPK pathways, thereby enhancing T-cell persistence and effector function.