The article discusses the role of 4-1BB, a costimulatory receptor on T cells, in immune responses and its potential as a target for immunotherapy. 4-1BB is a member of the TNFR superfamily and is expressed on various immune cells, including T cells, B cells, and dendritic cells. It plays a crucial role in T-cell activation, survival, and function by interacting with its ligand, 4-1BBL. However, the clinical development of 4-1BB agonist antibodies has been hindered by severe adverse events, particularly hepatotoxicity. Researchers are working to develop new agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while minimizing adverse effects. The article reviews the structure and function of 4-1BB and 4-1BBL, their roles in T-cell biology, and their clinical applications. It also discusses the structural differences between human and murine 4-1BB/4-1BBL complexes and the role of galectins in modulating 4-1BB signaling. The article highlights the metabolic regulation of T cells by 4-1BB, which is crucial for their proliferation and survival. It also explores the role of 4-1BB in CAR T-cell therapy, where it enhances T-cell persistence and memory formation. The article discusses the dual regulatory functions of the 4-1BB/4-1BBL pathway, which can both stimulate and inhibit T-cell responses depending on the context. It also reviews the development of agonistic anti-4-1BB antibodies, highlighting the challenges in translating these antibodies into clinical practice due to toxicity concerns. Recent advances in engineered proteins, including bispecific antibodies and recombinant proteins, are discussed as potential solutions to these challenges. The article concludes by emphasizing the importance of understanding the role of 4-1BB in both lymphoid and nonlymphoid tissues and the need for further research to optimize its use in immunotherapy. It also highlights the potential of combining 4-1BB agonists with other immune checkpoint inhibitors to enhance antitumor immunity and improve the effectiveness of cancer immunotherapy.The article discusses the role of 4-1BB, a costimulatory receptor on T cells, in immune responses and its potential as a target for immunotherapy. 4-1BB is a member of the TNFR superfamily and is expressed on various immune cells, including T cells, B cells, and dendritic cells. It plays a crucial role in T-cell activation, survival, and function by interacting with its ligand, 4-1BBL. However, the clinical development of 4-1BB agonist antibodies has been hindered by severe adverse events, particularly hepatotoxicity. Researchers are working to develop new agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while minimizing adverse effects. The article reviews the structure and function of 4-1BB and 4-1BBL, their roles in T-cell biology, and their clinical applications. It also discusses the structural differences between human and murine 4-1BB/4-1BBL complexes and the role of galectins in modulating 4-1BB signaling. The article highlights the metabolic regulation of T cells by 4-1BB, which is crucial for their proliferation and survival. It also explores the role of 4-1BB in CAR T-cell therapy, where it enhances T-cell persistence and memory formation. The article discusses the dual regulatory functions of the 4-1BB/4-1BBL pathway, which can both stimulate and inhibit T-cell responses depending on the context. It also reviews the development of agonistic anti-4-1BB antibodies, highlighting the challenges in translating these antibodies into clinical practice due to toxicity concerns. Recent advances in engineered proteins, including bispecific antibodies and recombinant proteins, are discussed as potential solutions to these challenges. The article concludes by emphasizing the importance of understanding the role of 4-1BB in both lymphoid and nonlymphoid tissues and the need for further research to optimize its use in immunotherapy. It also highlights the potential of combining 4-1BB agonists with other immune checkpoint inhibitors to enhance antitumor immunity and improve the effectiveness of cancer immunotherapy.