TNFSF9 Gene

HGNC Family	Tumor necrosis factor (ligand) superfamily (TNFSF)
Name	tumor necrosis factor (ligand) superfamily, member 9
Description	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]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFSF9, also known as 4–1BB ligand (4–1BBL) or CD137L, is a potent costimulatory molecule predominantly expressed by activated antigen‐presenting cells including dendritic cells, monocytes, and certain B‐cell subsets, as well as by some tumor cells. Engagement of TNFSF9 with its receptor 4–1BB (CD137) on activated T cells supports cellular activation, expansion, and survival; it enhances cytokine production (such as IL–2 and IFN–γ) and cytolytic effector function while also contributing to the reversal of T cell anergy. In addition, TNFSF9 contributes to both direct (autocostimulation) and indirect (transcostimulation) signaling across the immunological synapse, thereby amplifying T-cell responses and shaping adaptive immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in T-cell costimulation, TNFSF9 also transduces “reverse signals” into the cells that express it. Such reverse signaling can promote dendritic cell maturation, influence the production of inflammatory mediators (including TNF, IL–12, and IL–10), and affect the migration and polarization of macrophages, thereby contributing to sustained cytokine production and fine-tuning of immune responses. Moreover, these signaling events involve activation of downstream pathways—such as MAP kinases (e.g., p38, ERK), NF–κB, CREB, and others—that help regulate not only the timing of early versus late cytokine production following Toll-like receptor engagement but also modulate inflammatory responses in diverse contexts including sepsis, atherosclerosis, and certain malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe unique bidirectional properties of TNFSF9 have been exploited in clinical and therapeutic contexts. Strategies that engage TNFSF9—either through agonistic antibodies or through engineered fusion proteins integrating costimulatory domains—have demonstrated the ability to enhance ex vivo expansion of NK cells and CD8+ T cells, reverse T cell anergy, and potentiate antigen-specific anticancer responses. In various tumor models, including pancreatic, colorectal, and T-cell lymphomas, targeting the TNFSF9/4–1BB pathway has proven beneficial in reshaping the tumor microenvironment, overcoming immune evasion, and improving therapeutic outcomes by promoting robust T-cell and natural killer cell activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tao Wen, Jacob Bukczynski, Tania H Watts "}, {"type": "b", "children": [{"type": "t", "text": "4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.168.10.4897"}], "href": "https://doi.org/10.4049/jimmunol.168.10.4897"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11994439"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11994439"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Young-June Kim, Geling Li, Hal E Broxmeyer "}, {"type": "b", "children": [{"type": "t", "text": "4-1BB ligand stimulation enhances myeloid dendritic cell maturation from human umbilical cord blood CD34+ progenitor cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hematother Stem Cell Res (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/152581602321080556"}], "href": "https://doi.org/10.1089/152581602321080556"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12590704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12590704"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jacob Bukczynski, Tao Wen, Tania H Watts "}, {"type": "b", "children": [{"type": "t", "text": "Costimulation of human CD28- T cells by 4-1BB ligand."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/immu.200310020"}], "href": "https://doi.org/10.1002/immu.200310020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12645943"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12645943"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Camilla Reali, Monica Curto, Valeria Sogos, et al. 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Synonyms	CD137L, TNLG5A, 4-1BB-L
Proteins	TNFL9_HUMAN
NCBI Gene ID	8744
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

TNFSF9 has 8,338 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 112 datasets.

Click the + buttons to view associations for TNFSF9 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

TNFSF9 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TNFSF9 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of TNFSF9 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of TNFSF9 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of TNFSF9 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TNFSF9 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving TNFSF9 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of TNFSF9 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TNFSF9 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TNFSF9 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of TNFSF9 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of TNFSF9 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of TNFSF9 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with TNFSF9 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TNFSF9 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of TNFSF9 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of TNFSF9 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of TNFSF9 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of TNFSF9 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing TNFSF9 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with TNFSF9 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with TNFSF9 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of TNFSF9 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with TNFSF9 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with TNFSF9 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with TNFSF9 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with TNFSF9 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of TNFSF9 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by TNFSF9 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with TNFSF9 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with TNFSF9 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with TNFSF9 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with TNFSF9 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at TNFSF9 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TNFSF9 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of TNFSF9 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing TNFSF9 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with TNFSF9 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with TNFSF9 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of TNFSF9 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with TNFSF9 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.