TNFRSF9

Overview

TNFRSF9 encodes 4-1BB, also known as CD137, a member of the tumor necrosis factor receptor superfamily. It is an inducible cell-surface costimulatory receptor expressed primarily on activated T cells and other immune cells, where it helps amplify immune activation, support cell survival, and promote effector function. Because of these properties, TNFRSF9 is widely studied in cancer immunology and immunotherapy as both a biomarker of immune activation and a therapeutic target.

In biomedical research, TNFRSF9 is especially relevant to CAR-T-cell engineering and 4-1BB agonistic monoclonal antibody development. The receptor is used as a costimulatory module in many chimeric antigen receptor designs, and its signaling has been investigated for effects on T-cell persistence, metabolic fitness, proliferation, and antitumor activity. It is also being explored in the context of immune checkpoint modulation and inflammatory immune states, including regulatory T-cell phenotypes.

Recent Publications Focus

Below is a summary of the newest research publications targeting TNFRSF9 (sorted by publication date).

Recent studies have continued to examine TNFRSF9/CD137 as a key immunologic node in both engineered cell therapy and immune regulation. In preclinical CAR-T-cell research, multiple groups used 4-1BB-co-stimulated CAR-T cells to improve antitumor performance. One study on αvβ3 CAR-T cells in melanoma and triple-negative breast cancer tested two CAR designs, one containing CD28 and the other 4-1BB co-stimulation, to evaluate how costimulatory signaling affected control of primary tumors and metastases. Another preclinical proof-of-concept study in synovial sarcoma constructed NKG2D-based CAR-T cells with 4-1BB co-stimulation, reflecting the continued use of TNFRSF9 signaling to support engineered T-cell function.

Mechanistic work has also focused on how TNFRSF9-related signaling shapes CAR-T-cell fate. A study in Nature Immunology investigated how asymmetric cell division and chromatin accessibility are influenced by CAR costimulatory domains, emphasizing that approved CAR-T-cell products use either 4-1BB or CD28 and that these signals drive distinct early fate decisions. Related work in myeloma and lymphoma models showed that endogenous CD28 on 4-1BB costimulated CAR T cells can prolong in vivo activity, improve mitochondrial metabolism and redox balance, and enhance proliferation and inflammatory cytokine release in the tumor microenvironment. A companion report described endogenous CD28 signaling as a regulator of 4-1BB CAR T-cell function, promoting metabolic fitness, proliferation, and sustained antitumor activity. Together, these studies highlight that TNFRSF9-based CAR designs do not act in isolation; their effects are shaped by broader costimulatory networks, including CD28 and T-cell receptor signaling.

Clinical and translational publications also referenced TNFRSF9 in the context of CAR-T-cell manufacturing and product quality. In a report on idecabtagene vicleucel manufacturing and out-of-specification products in relapsed and refractory multiple myeloma, high CD137 activation was noted as a common reason for product deviation, alongside low infused dose. Another long-term outcomes study of CNCT19 in aggressive B-cell lymphoma described the product as a second-generation CAR T-cell with a 4-1BB costimulatory domain, reinforcing the clinical relevance of TNFRSF9-based signaling in approved and investigational CAR platforms. Additional work in pancreatic tumor models reported that treatment with GNE-495 reduced expression of the 4-1BB gene in both peripheral and tumor-infiltrating T cells, suggesting that the tumor immune landscape can modulate TNFRSF9-associated activation states.

TNFRSF9 has also been studied outside CAR-T-cell engineering as an immune checkpoint-like regulator in T-cell subsets. A report in The Journal of Clinical Investigation identified a subset of regulatory T cells coexpressing CD137 and IL6R, termed atypical Tregs, which were selectively enriched in patients with checkpoint inhibitor-associated arthritis. In a separate study in The Journal of Experimental Medicine, both soluble and cell-surface CD137 expressed by Foxp3+ CD4 T cells were shown to restrain autoimmune diabetes, underscoring a role for TNFRSF9 in immune tolerance and autoimmune control. These findings indicate that TNFRSF9 can contribute not only to immune activation but also to immunoregulatory programs depending on cellular context.

Finally, TNFRSF9 remains a major target in broader therapeutic development. A review of next-generation 4-1BB agonists discussed the limitations of first-generation agents such as urelumab and utomilumab and the ongoing effort to engineer molecules with improved safety and efficacy. Across these studies, TNFRSF9/CD137 emerges as a central receptor at the intersection of T-lymphocyte activation, tumor immunotherapy, regulatory T-cell biology, and immune-related toxicity, making it a persistent focus of translational immunology research.

Background PMIDs

• [PMID 41645963]

Method PMIDs

• [PMID 41793303]
• [PMID 42259140]
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Target PMIDs

• [PMID 42332264]
• [PMID 42383349]
• [PMID 41894689]
• [PMID 41627211]
• [PMID 41848361]
• [PMID 41707980]
• [PMID 42412561]