{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFRSF9, also known as CD137 or 4‑1BB, is a member of the tumor necrosis factor receptor superfamily that is transiently expressed on activated lymphocytes—including T cells, natural killer cells, and even nonimmune cells such as endothelial and neural cells—and plays a critical role in costimulatory signaling. Engagement of TNFRSF9 by its ligand or agonistic antibodies promotes lymphocyte activation, proliferation, and survival by inducing key signaling pathways (e.g., via NF‑κB and anti‐apoptotic mediators) and by enhancing cytokine secretion, thereby shaping effector and memory cell responses. This receptor is also rapidly upregulated on antigen‐stimulated or virus‐specific T cells, making it a sensitive marker for isolating activated as well as alloreactive T cells in diverse immunologic and clinical settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of adoptive immunotherapy and chimeric antigen receptor (CAR) T‑cell strategies, TNFRSF9 costimulation has emerged as a pivotal regulatory element. Incorporation of TNFRSF9 signaling domains into CAR constructs enhances T‑cell expansion, persistence, and antitumor efficacy by sustaining noncanonical NF‑κB activation and by promoting the generation of central memory and effector subsets with a preferential Th1 cytokine profile. Moreover, agonistic targeting of TNFRSF9 can rescue T‑cell populations from exhaustion, augment natural killer cell function, and even improve the expansion and functional stability of regulatory T cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in promoting lymphocyte activation and survival, TNFRSF9 is instrumental in modulating the tumor microenvironment and in maintaining immune homeostasis. Its expression on infiltrating T cells within lymphomas and solid tumors not only serves as an important prognostic biomarker but also can influence therapeutic responses, as seen in the improvement of antibody‐mediated cytotoxicity and in the recruitment and modulation of dendritic cells. Mutations in TNFRSF9 are associated with impaired T‑cell expansion and the development of virus‐associated lymphoproliferative disorders, underscoring its essential function in host immunity. Structural studies have revealed that TNFRSF9 forms disulfide‐linked dimers that, through multivalent binding to its ligand, can amplify downstream costimulatory signals—a property being exploited in novel oncolytic and combination immunotherapies—while soluble forms of the receptor are emerging as potential biomarkers in inflammatory and cardiovascular diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Diego Laderach, Mojgan Movassagh, Anthony Johnson, et al. 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