TNFRSF9 (4-1BB/CD137) is a TNF receptor superfamily member that functions as a co-stimulatory receptor on T cells, playing a crucial role in immune activation and cancer immunotherapy. The receptor enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity when bound by its ligand TNFSF9/4-1BBL 1. In tumor contexts, TNFRSF9 expression serves as an activation marker, with bimodal distribution observed in regulatory T cells (Tregs) within non-small-cell lung cancer, where activated TNFRSF9+ Tregs correlate with poor prognosis 2. The receptor is extensively utilized in chimeric antigen receptor (CAR) T-cell therapies, where 4-1BB co-stimulation promotes superior antitumor activity by reducing PD-1 expression and preventing T-cell exhaustion compared to CD28 co-stimulation 34. Clinical studies demonstrate that 4-1BB-based CAR-T cells show greater persistence and reduced toxicity profiles, though with potentially different efficacy patterns compared to CD28-based constructs 5. The receptor's therapeutic potential extends beyond CAR-T applications, as engineered 4-1BB agonists are being developed for direct cancer immunotherapy, with low-affinity variants showing enhanced clustering and improved immune activation 67.