4-1BB immunotherapy has emerged as a crucial receptor in T-cell-mediated immune functions. Despite its promise in in vivo tumor models, clinical development has been hindered by severe adverse events, particularly hepatotoxicity. Researchers are now developing new generations of agonist antibodies and recombinant proteins with modified effector functions to harness 4-1BB's potent T-cell modulation properties while minimizing side effects. This review examines the role of 4-1BB in T-cell biology, its clinical applications, and future prospects in 4-1BB agonist immunotherapy. 4-1BB, also known as CD137 or TNF receptor superfamily member 9 (TNFRSF9), is a glycosylated type I membrane protein and a member of the TNFR superfamily. It is expressed on T cells, B cells, macrophages, natural killer (NK) cells, and dendritic cells (DCs), with splenic DCs constitutively expressing it. Inducible expression is primarily restricted to activated T cells. 4-1BB enhances T-cell responses to antigens by recruiting TRAF adaptor proteins to cytosolic TRAF-binding motifs, initiating costimulatory signaling. This signaling enhances T-cell survival by suppressing activation-induced cell death (AICD) and synergizes with CD28 costimulation to enhance cytokine production by activated T cells. The ligand for 4-1BB is 4-1BBL (also known as TNFSF9 or CD137L). 4-1BBL is a type II membrane protein of the TNF superfamily. It is constitutively expressed in splenic DCs and upregulated on spleen germinal center B cells, macrophages, and antigen-presenting cells (APCs) after activation. 4-1BBL is also expressed on tumor cells of various origins, such as carcinoma and colon cancers. This suggests a role for 4-1BB/4-1BBL signaling in shaping immunity in both lymphoid and nonlymphoid organs. The structure of the 4-1BB/4-1BBL complex is characterized by a single transmembrane domain, an extracellular domain with disulfide bond-stabilized cysteine-rich domains (CRDs) for ligand binding, and an intracellular signaling domain containing different motifs for signal transduction. These CRDs form a characteristic 'jellyroll' fold consisting of two beta sheets held together by disulfide bonds. Human 4-1BB/4-1BBL binds in a heterohexameric conformation where the trimer formed by 4-1BBL binds with three molecules of 4-1BB. This allows the formation of a 2D lattice structure of 4-1BB and 4-1BBL molecules, facilitating strong 4-1BB signaling4-1BB immunotherapy has emerged as a crucial receptor in T-cell-mediated immune functions. Despite its promise in in vivo tumor models, clinical development has been hindered by severe adverse events, particularly hepatotoxicity. Researchers are now developing new generations of agonist antibodies and recombinant proteins with modified effector functions to harness 4-1BB's potent T-cell modulation properties while minimizing side effects. This review examines the role of 4-1BB in T-cell biology, its clinical applications, and future prospects in 4-1BB agonist immunotherapy. 4-1BB, also known as CD137 or TNF receptor superfamily member 9 (TNFRSF9), is a glycosylated type I membrane protein and a member of the TNFR superfamily. It is expressed on T cells, B cells, macrophages, natural killer (NK) cells, and dendritic cells (DCs), with splenic DCs constitutively expressing it. Inducible expression is primarily restricted to activated T cells. 4-1BB enhances T-cell responses to antigens by recruiting TRAF adaptor proteins to cytosolic TRAF-binding motifs, initiating costimulatory signaling. This signaling enhances T-cell survival by suppressing activation-induced cell death (AICD) and synergizes with CD28 costimulation to enhance cytokine production by activated T cells. The ligand for 4-1BB is 4-1BBL (also known as TNFSF9 or CD137L). 4-1BBL is a type II membrane protein of the TNF superfamily. It is constitutively expressed in splenic DCs and upregulated on spleen germinal center B cells, macrophages, and antigen-presenting cells (APCs) after activation. 4-1BBL is also expressed on tumor cells of various origins, such as carcinoma and colon cancers. This suggests a role for 4-1BB/4-1BBL signaling in shaping immunity in both lymphoid and nonlymphoid organs. The structure of the 4-1BB/4-1BBL complex is characterized by a single transmembrane domain, an extracellular domain with disulfide bond-stabilized cysteine-rich domains (CRDs) for ligand binding, and an intracellular signaling domain containing different motifs for signal transduction. These CRDs form a characteristic 'jellyroll' fold consisting of two beta sheets held together by disulfide bonds. Human 4-1BB/4-1BBL binds in a heterohexameric conformation where the trimer formed by 4-1BBL binds with three molecules of 4-1BB. This allows the formation of a 2D lattice structure of 4-1BB and 4-1BBL molecules, facilitating strong 4-1BB signaling