The 4-1BB ligand (4-1BBL), encoded by the TNFSF9 gene, is a type II transmembrane glycoprotein of the tumor necrosis factor (TNF) ligand superfamily, primarily expressed on antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells, with expression inducible upon activation ^[1]. The gene, located on chromosome 19p13.3 in humans, encodes a trimeric protein that binds to the 4-1BB (CD137/TNFRSF9) receptor. 4-1BB is expressed on activated T lymphocytes (CD4+ and CD8+ T cells), as well as natural killer (NK) cells, NKT cells, and certain myeloid cells, including monocytes, neutrophils, and mast cells. The primary function of the 4-1BB/4-1BBL interaction is to deliver a crucial co-stimulatory signal to T cells, augmenting their activation, proliferation, survival, and cytokine production, particularly enhancing cytotoxic T lymphocyte (CTL) activity, which is vital for effective anti-tumor responses and antiviral immunity ^[2-3]. Dysregulation of 4-1BB/4-1BBL signaling has been implicated in various diseases, including cancer, where its activation promotes anti-tumor immunity, and autoimmune disorders, where its modulation can impact inflammatory responses ^[4]. In drug development, 4-1BBL’s costimulatory potential has been harnessed in cancer immunotherapy, with recombinant forms like SA-4-1BBL showing promise in preclinical models for enhancing anti-tumor immunity ^[5]. The researchers focus on enhancing T cell responses while mitigating adverse reactions, such as hepatotoxicity, observed in early-phase clinical trials.

The B6-h4-1BB-L (hTNFSF9) mouse is a humanized model constructed by in situ replacement of the coding sequence of the murine endogenous Tnfsf9 gene with that of the human TNFSF9 gene. This model can be used in studies of cancer immunotherapy and autoimmune diseases, as well as in the screening, development, and safety evaluation of 4-1BB-L-targeted drugs.