not-yet-known not-yet-known not-yet-known unknown 3.3 CD137 (4-1BB) CD137, also known as 4-1BB (4-1BBR or TNFRSF9) was first cloned in 1989 using a differential screening method from mouse cDNA libraries [304], is a co-stimulatory receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily. It is primarily expressed on activated T cells (CD4+ and CD8+ T cells) and natural killer (NK) cells, where it plays a crucial role in regulating immune responses [305]. Upon engagement with its ligand (4-1BBL), which is expressed on antigen-presenting cells (APCs) and other immune cells, CD137 delivers potent co-stimulatory signals to T cells (CD8+ > CD4+  T cells) and NK cells [304, 306]. This interaction supports T cell proliferation, survival, and the formation of memory T cells. CD137’s prefrential proliferation of CD8+ T cells makes it an especially appealing target for anti-cancer therapies. Moreover, CD137 signaling can activate dendritic cells and NK cells, which further aids in cytotoxic T cell activation [304, 306, 307]. It can additionally induce proliferation in peripheral monocytes, enhance T cell apoptosis triggered by TCR/CD3 activation, and regulate CD28 co-stimulation to promote Th1 cell responses.CD137 synergizes with CD28 costimulation, also enhancing the production of cytokines such as interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), which are essential for orchestrating robust immune responses against infections and tumors [307, 308, 309]. CD137 agonists aim to enhance anti-tumor immune responses by stimulating T cell and NK cell cytotoxicity against tumor cells as seen in a study by Gauttier et al. [310]. Further, in a mouse model of malignant melanoma, the anti-CD137 antibody prevents cancer recurrence and metastasis following the removal of primary tumors by expanding antigen-specific memory T lymphocytes [311]. First generation agonistic antibodies, Urelumab (BMS-663513) and Utomilumab (PF-05082566) which can activate CD137, had been developed and investigated in preclinical and clinical studies [312]. While it’s evident that these anti-4-1BB antibodies are outstanding at curbing tumor growth in diverse in vivo mouse models, a significant hurdle remains: developing a strategy to translate this anti-4-1BB immunotherapy into clinical settings with a manageable toxicity profile [313]. The Phase I clinical trial assessing the safety of urelumab (an agonist antibody targeting CD137) revealed significant transaminitis, which was strongly linked to doses of 1 mg/kg or higher [314]. In another Phase Ib Study, Utomilumab (PF-05082566) (also a agonist antibody targeting CD137) in combination with Pembrolizumab (MK-3475), only 26.1% patients had confirmed complete or partial responses, although there were very low incidence of toxicities [315]. Current research is centered on adjusting the functions of 4-1BB antibodies. Yu et al. created a lower affinity variant of utomilumab, converting it from an inert antibody into a highly effective agonistic antibody [316]. Between 2017 - 2022, at least 41 4–1BB agonistic drugs have progressed to Phase 1 clinical trials, according to published reports and data from the U.S. National Library of Medicine’s clinicaltrials.gov registry, the Chinese Clinical Trial Registry, and the European Union Trial Register, at least 41 4–1BB agonistic drugs have entered Phase 1 clinical trials [312].