TNFSF9

Official Full Name

TNF superfamily member 9

Organism

Homo sapiens

GeneID

8744

Background

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This transmembrane cytokine is a bidirectional signal transducer that acts as a ligand for TNFRSF9/4-1BB, which is a costimulatory receptor molecule in T lymphocytes. This cytokine and its receptor are involved in the antigen presentation process and in the generation of cytotoxic T cells. The receptor TNFRSF9/4-1BB is absent from resting T lymphocytes but rapidly expressed upon antigenic stimulation. The ligand encoded by this gene, TNFSF9/4-1BBL, has been shown to reactivate anergic T lymphocytes in addition to promoting T lymphocyte proliferation. This cytokine has also been shown to be required for the optimal CD8 responses in CD8 T cells. This cytokine is expressed in carcinoma cell lines, and is thought to be involved in T cell-tumor cell interaction.[provided by RefSeq, Oct 2008]

Synonyms

CD137L; TNLG5A; 4-1BB-L;

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Detailed Information

The TNFSF9 gene encodes 4-1BB Ligand (4-1BBL), a member of the tumor necrosis factor (TNF) superfamily. Located on human chromosome 19p13.3, TNFSF9 encodes a type II transmembrane protein, with its N-terminus in the cytoplasm and its C-terminal TNF homology domain extracellularly. As a typical TNF family ligand, TNFSF9 exists as a homotrimer on the cell membrane, a multimeric structure essential for receptor binding and downstream signaling activation. TNFSF9 can also be cleaved by proteases, releasing a soluble trimer with biological activity. Its only known receptor, TNFRSF9 (also known as 4-1BB or CD137), is an important costimulatory molecule primarily expressed on activated T lymphocytes, especially CD8⁺ cytotoxic T cells, as well as NK cells and dendritic cells. The TNFSF9-TNFRSF9 interaction forms a critical axis in immune co-stimulation, regulating the strength and durability of adaptive immune responses, particularly T cell-mediated cellular immunity.

Biological Significance

The primary biological role of TNFSF9 lies in providing a key co-stimulatory signal to T cells. Following TCR-mediated recognition of antigen presented by antigen-presenting cells (APCs), T cells rapidly upregulate surface TNFRSF9 expression. Concurrent engagement with TNFSF9 on APCs or neighboring cells transmits a robust secondary (co-stimulatory) signal, activating NF-κB, MAPK, and other downstream pathways. This signal markedly enhances T cell clonal expansion, survival, cytokine production, and functional differentiation. TNFSF9-TNFRSF9 signaling is particularly critical for the activation and maintenance of CD8⁺ cytotoxic T cells, preventing activation-induced cell death and promoting memory T cell formation, thereby supporting durable anti-tumor and antiviral immunity.

In addition to enhancing naïve T cell activation, TNFSF9 can reactivate exhausted or anergic T cells, a state commonly induced by chronic infection or the tumor microenvironment. Co-stimulation via TNFSF9 partially reverses exhaustion, restoring effector function, which provides a strong rationale for immunotherapeutic applications. The pathway also regulates interactions between T cells and other immune cells, such as B cells and macrophages, affecting both humoral and innate immunity. In the tumor microenvironment, TNFSF9 expression by tumor cells may occur, but the resultant co-stimulatory signaling with T cell-expressed TNFRSF9 generally promotes anti-tumor immunity, establishing this axis as a highly attractive therapeutic target.

Figure 1. SA-4-1BBL activates the non-canonical NF-κB pathway via TNFR. (Martinez-Perez AG, et al., 2021)

Clinical Relevance

Clinical exploration of the TNFSF9/TNFRSF9 axis focuses primarily on cancer immunotherapy, aiming to agonize this co-stimulatory pathway to boost patient T cell anti-tumor responses. Most development efforts target TNFRSF9 with agonistic antibodies. These antibodies mimic, or even exceed, the natural 4-1BBL signal by crosslinking TNFRSF9 on T cells, delivering potent co-stimulatory signals that enhance T cell activation, proliferation, survival, and reversal of exhaustion. Preclinical models demonstrate robust anti-tumor effects, whether administered alone or in combination with chemotherapy, radiotherapy, or other immune checkpoint inhibitors.

Translating these approaches clinically presents challenges. Early trials observed serious adverse events, such as hepatotoxicity, indicating that systemic administration of potent co-stimulatory agonists requires careful dosing and regimen optimization. New strategies under investigation include bispecific antibodies that target both TNFRSF9 and tumor-associated antigens to concentrate co-stimulation in tumor-infiltrating T cells, and formulations that locally enrich the agonist at tumor sites. TNFSF9 also has potential in CAR-T therapy, where co-expression may enhance CAR-T cell persistence and function via autocrine or paracrine mechanisms. Beyond cancer, the TNFSF9/TNFRSF9 pathway may be relevant in autoimmune and inflammatory diseases, where excessive co-stimulation could drive pathogenic T cell activation; in these contexts, antagonistic approaches could have therapeutic value, though research remains limited.

In conclusion, a detailed understanding of TNFSF9 biology establishes it as a critical immunotherapy target, with successful clinical translation dependent on precise control of signaling and careful optimization of therapeutic strategies.

References

Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol. 2009;9(4):271-285.
Chester C, Sanmamed MF, Wang J, et al. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood. 2018;131(1):49-57.
Wang C, Lin GH, McPherson AJ, et al. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev. 2009 May;229(1):192-215.
Martinez-Perez AG, Perez-Trujillo JJ, Garza-Morales R, et al. 4-1BBL as a Mediator of Cross-Talk between Innate, Adaptive, and Regulatory Immunity against Cancer. Int J Mol Sci. 2021 Jun 9;22(12):6210.

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