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Tumor necrosis factor receptor 2
Tumor necrosis factor receptor 2
Tumor necrosis factor receptor 2
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TNFRSF1B
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTNFRSF1B, CD120b, TBPII, TNF-R-II, TNF-R75, TNFBR, TNFR1B, TNFR2, TNFR80, p75, p75TNFR, tumor necrosis factor receptor superfamily member 1B, TNF receptor superfamily member 1B
External IDsOMIM: 191191; MGI: 1314883; HomoloGene: 829; GeneCards: TNFRSF1B; OMA:TNFRSF1B - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7133

21938

Ensembl

ENSG00000028137

ENSMUSG00000028599

UniProt

P20333

P25119

RefSeq (mRNA)

NM_001066

NM_011610

RefSeq (protein)

NP_001057

NP_035740

Location (UCSC)Chr 1: 12.17 – 12.21 MbChr 4: 144.94 – 144.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) and CD120b, is one of two membrane receptors that binds tumor necrosis factor-alpha (TNFα).[5][6] Like its counterpart, tumor necrosis factor receptor 1 (TNFR1), the extracellular region of TNFR2 consists of four cysteine-rich domains which allow for binding to TNFα.[7][8] TNFR1 and TNFR2 possess different functions when bound to TNFα due to differences in their intracellular structures, such as TNFR2 lacking a death domain (DD).[7]

Function

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The protein encoded by this gene is a member of the tumor necrosis factor receptor superfamily, which also contains TNFRSF1A. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2 (TRAF2), which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways.[9]

Clinical significance

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CNS

[edit]

At least partly because TNFR2 has no intracellular death domain, TNFR2 is neuroprotective.[10]

Patients with schizophrenia have increased levels of soluble tumor necrosis factor receptor 2 (sTNFR2).[11]

Cancer

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Targeting of TNFR2 in tumor cells is associated with increased tumor cell death and decreased progression of tumor cell growth.[8]

Increased expression of TNFR2 is found in breast cancer, cervical cancer, colon cancer, and renal cancer.[8] A link between the expression of TNFR2 in tumor cells and late-stage cancer has been discovered.[8] TNFR2 plays a significant role in tumor cell growth as it has been found that the loss of TNFR2 expression is linked with increased death of associated tumor cells and a significant standstill of further growth.[8] There is therapeutic potential in the targeting of TNFR2 for cancer treatments through TNFR2 inhibition.[12]

Systemic Lupus Erythematous (SLE)

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A small scale study of 289 Japanese patients suggested a minor increased predisposition from an amino acid substitution of the 196 allele at exon 6. Genomic testing of 81 SLE patients and 207 healthy patients in a Japanese study showed 37% of SLE patients had a polymorphism on position 196 of exon 6 compared to 18.8% of healthy patients. The TNFR2 196R allele polymorphism suggests that even one 196R allele results in increased risk for SLE.[13]

Interactions

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TNFRSF1B has been shown to interact with:

References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Tumor necrosis factor receptor 2

View on Grokipedia
from Grokipedia
Tumor necrosis factor receptor 2 (TNFR2), encoded by the TNFRSF1B gene, is a type I transmembrane protein belonging to the tumor necrosis factor receptor superfamily that primarily binds alpha (TNF-α), as well as (LT-α) and progranulin, to mediate signaling pathways focused on cell survival, proliferation, and immune modulation rather than . Unlike its counterpart TNFR1, TNFR2 lacks a domain in its cytoplasmic tail, enabling it to preferentially recruit TNF receptor-associated factor 2 (TRAF2) and cellular inhibitors of (cIAP1/2) to activate non-canonical pathways that promote anti-inflammatory and regenerative responses. Expressed on a range of cell types including regulatory T cells (Tregs), endothelial cells, , neurons, and tumor-associated immune cells, TNFR2 plays a pivotal role in maintaining immune and tissue repair. TNFR2 features an extracellular domain with four cysteine-rich subdomains for ligand binding, a transmembrane helix, and an intracellular domain that facilitates TRAF2-dependent signaling without inducing cell death. Upon ligand binding—particularly the membrane-bound form of TNF-α, which preferentially activates TNFR2 signaling compared to the soluble form—TNFR2 oligomerizes and initiates cascades involving nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 3 (STAT3) pathways, all of which support cell proliferation, migration, and survival. This contrasts with TNFR1's pro-apoptotic tendencies via death domain recruitment, highlighting TNFR2's specialized function in adaptive immunity and inflammation resolution. Expression is broadly distributed but inducible, with high levels in lymphoid tissues like the spleen and appendix, and upregulated in response to cytokines such as interleukin-6 in pathological contexts. In immune regulation, TNFR2 is essential for the expansion and suppressive function of Tregs, where it enhances expression and inhibits autoreactive T cells, thereby preventing excessive and . Dysregulation, such as polymorphisms or overexpression, has been implicated in autoimmune diseases including , , and , where it contributes to chronic and tissue damage. In cancer, TNFR2 promotes tumor progression by fostering an immunosuppressive through Treg and myeloid-derived suppressor cell activation, via endothelial cells, and direct enhancement of proliferation and in malignancies like colorectal, , and cancers. Conversely, its role in neuronal protection and tissue regeneration—evident in models of cardiac repair, pancreatic islet recovery, and maintenance—positions TNFR2 as a therapeutic target, with agonists showing promise for and antagonists for to disrupt tumor immune evasion. As of 2025, TNFR2-targeted therapies, including agonists for autoimmune diseases and antagonists for solid tumors, are advancing in phase 1 and 2 clinical trials.

Molecular Biology

Gene Characteristics

The TNFRSF1B , which encodes tumor necrosis factor receptor 2 (TNFR2), is located on the short arm of human at cytogenetic band p36.22, spanning genomic coordinates 12,166,991–12,209,220 (GRCh38 assembly), a region of approximately 42 kb. The orthologous in mice, Tnfrsf1b, resides on at positions 144,940,033–144,973,440 (GRCm39 assembly). The gene consists of 10 exons in its canonical transcript (ENST00000376259.9), encoding a 461-amino-acid precursor protein that includes a , extracellular domains, a transmembrane region, and an intracellular signaling domain. of TNFRSF1B transcripts can produce soluble isoforms of TNFR2 (sTNFR2), which lack the transmembrane and cytoplasmic domains and function as receptors to modulate TNF signaling. TNFRSF1B exhibits constitutive low-level expression across most human tissues, with higher baseline levels in , , and immune cells such as T lymphocytes and endothelial cells. Its expression is upregulated by inflammatory cytokines including TNF-α, IL-1β, and IFN-γ, which bind to promoter regions and activate distal enhancers to drive transcription in response to immune challenges. Tissue-specific patterns are regulated by cis-regulatory elements, including NF-κB-responsive promoters and inducible enhancers that integrate signals from the inflammatory microenvironment. Evolutionary conservation of TNFRSF1B is evident across vertebrates, with over 300 orthologs identified, reflecting its fundamental role in inflammation and immune regulation; for example, human and mouse proteins share approximately 62% amino acid sequence identity, with higher similarity (>80%) in the extracellular cysteine-rich domains critical for ligand binding.

Protein Structure

Tumor necrosis factor receptor 2 (TNFR2), also known as TNFRSF1B, is a type I transmembrane glycoprotein composed of 439 amino acids in its mature form following cleavage of the N-terminal signal peptide, with an approximate molecular weight of 75 kDa due to extensive glycosylation. The protein's architecture is divided into three principal regions: an extracellular ligand-binding domain, a transmembrane-spanning segment, and an intracellular signaling domain. This organization facilitates TNFR2's role in transducing signals from the cytokine tumor necrosis factor alpha (TNF-α), encoded by the TNFRSF1B gene (see Gene Characteristics). The extracellular domain encompasses the first 235 amino acids and is characterized by four cysteine-rich domains (CRDs 1–4), each approximately 40 long and stabilized by bonds formed by conserved cysteine residues. CRD1 and CRD4 contribute to overall structural integrity and positioning, while CRD2 and CRD3 are essential for conferring specificity and high-affinity binding to membrane-bound TNF-α homotrimers, enabling TNFR2's preferential activation by transmembrane forms of the over soluble TNF-α (see Ligand Binding and Activation). The domain also contains multiple N-linked sites, which promote protein stability, prevent aggregation, and modulate accessibility. The consists of a single α-helical stretch of about 30 hydrophobic that anchors TNFR2 in the plasma membrane, facilitating signal transmission across the . In contrast, the intracellular domain comprises the C-terminal 174 and notably lacks a death domain, unlike its counterpart TNFR1, which precludes direct activation of caspase-dependent pathways. Instead, this region is enriched with motifs for adaptor protein recruitment, including multiple TRAF-binding sites conforming to the PXQXT/S (where X is any ), particularly prominent near the membrane-proximal area, which selectively engage TRAF2 to initiate non-canonical and MAPK signaling. Prior to ligand engagement, TNFR2 assembles into constitutive dimers via interactions in the pre-ligand assembly domain (PLAD) within CRD1, maintaining a poised state on the cell surface. binding induces higher-order trimerization, clustering three receptor dimers around a single TNF-α trimer and stabilizing the signaling complex through conformational changes in the transmembrane and intracellular domains. This dynamic oligomerization is crucial for amplifying downstream signals, with further enhancing receptor and functional integrity.

Mechanism of Action

Ligand Binding and Activation

Tumor necrosis factor receptor 2 (TNFR2) primarily interacts with tumor necrosis factor-alpha (TNF-α) as its main , binding both membrane-bound and soluble forms, with a (K_d) of approximately 0.42 nM for soluble TNF-α, which represents lower affinity compared to TNFR1 but higher affinity for the membrane-bound form. TNFR2 also binds lymphotoxin-α (LT-α) homotrimers. TNFR2 also binds progranulin, which acts as an to TNF-α signaling. The binding mechanism involves the trimeric TNF-α ligand engaging three TNFR2 molecules simultaneously, which induces a conformational change in the receptor extracellular domains and promotes receptor clustering on the cell surface. This interaction primarily occurs through cysteine-rich domains (CRDs) 2 and 3 of TNFR2, while CRD4 contributes to affinity and CRD1 serves to stabilize the complex but is not essential for achieving high-affinity binding. Upon binding, TNFR2 undergoes trimerization that exposes its intracellular signaling domain, initiating ; however, TNFR2 can also exhibit low-level constitutive signaling through pre-formed dimers mediated by the pre-ligand assembly domain (PLAD) within CRD1. Additionally, can be regulated by ectodomain shedding, where the ADAM17 (also known as TACE) cleaves the extracellular portion of TNFR2, generating a soluble form that acts as a receptor to sequester TNF-α and attenuate signaling. TNFR2 demonstrates selectivity by preferentially binding membrane-bound TNF-α over the soluble form, in contrast to TNFR1 which favors soluble TNF-α, thereby enabling context-specific activation in cell-cell interactions.

Downstream Signaling Pathways

Upon ligand-induced trimerization, TNFR2 recruits adaptor proteins TRAF2 and TRAF5 through specific intracellular binding motifs, initiating intracellular signaling without involvement of due to the absence of a death domain. This recruitment assembles a signaling complex that activates the canonical pathway, where TRAF2 associates with cIAP1/2 to mediate K63-linked ubiquitination of downstream effectors, leading to and activation of the IKK complex. The activated IKK phosphorylates , resulting in its degradation and nuclear translocation of p65/RelA-p50 dimers to drive transcription of pro-survival and inflammatory genes. Additionally, TNFR2 promotes non-canonical activation by facilitating TRAF2-cIAP1/2 degradation via K48-linked ubiquitination, which stabilizes NIK and enables IKKα-mediated processing of p100 to p52, culminating in RelB-p52 dimer translocation. TNFR2 signaling branches into pro-survival pathways, including activation of the MAPK cascade through TRAF2, which stimulates ERK, JNK, and p38 kinases to promote and production. The PI3K/Akt pathway is also engaged downstream of TNFR2, enhancing cell survival, migration, and metabolic reprogramming via phosphorylation of Akt and downstream targets like . Furthermore, the TRAF2-cIAP1/2 complex exerts anti-apoptotic effects by ubiquitinating and degrading pro-apoptotic substrates, such as and , while upregulating anti-apoptotic proteins like cFLIP; the lack of a death domain in TNFR2 precludes recruitment and activation, reinforcing survival signals. These mechanisms collectively inhibit extrinsic and support tissue repair. Crosstalk between TNFR2 and TNFR1 occurs through shared TRAF2 and cIAP1/2 adaptors, where TNFR2 can amplify TNFR1-mediated canonical signaling under co-stimulation but also deplete TRAFs to modulate cell fate. Outcomes are context-dependent: in regulatory T cells (Tregs), TNFR2 drives proliferation and suppressive function via and PI3K/Akt, whereas in macrophages, it can promote inflammatory responses through MAPK and activation.

Biological Roles

Immune System Regulation

TNFR2 plays a pivotal role in modulating T cell responses, particularly through its selective expression on (Tregs), where it promotes their expansion, survival, and suppressive function. TNFR2 signaling prevents at the promoter, thereby stabilizing expression and enabling Tregs to resolve while preventing . In TNFR2-deficient models, Tregs exhibit reduced stability and impaired suppressive capacity, underscoring TNFR2's necessity for Treg . TNF-α binding to TNFR2 activates these ⁺⁺TNFR2⁺ Tregs, which represent a highly suppressive subset comprising about 40% of peripheral Tregs in mice, enhancing their proliferation via non-canonical pathways that support IL-2-induced expansion. In myeloid cells, TNFR2 drives polarization and functional maturation. For macrophages, TNFR2 activation by progranulin (PGRN) or (GRN) upregulates M2-like phenotypes, promoting tissue repair and dampening excessive inflammation in contexts such as pulmonary and . This shift involves enhanced expression of markers and reduced pro-inflammatory output, balancing immune responses. In dendritic cells (DCs), TNFR2 contributes to survival and modulates production, including IL-6 and IL-10, which support tolerogenic functions and prevent overactivation during immune challenges. TNFR2 also influences dynamics, particularly in supporting production. Expression of TNFR2 on proliferating s and plasma blasts correlates with increased IL-10 secretion and enhanced cell viability, facilitating without excessive inflammation. This receptor identifies IL-10-producing regulatory s, which help maintain . Overall, TNFR2 balances pro- and anti-inflammatory responses by preferentially activating immunosuppressive populations, making it critical for induction. Recent studies highlight its role in tolerance, where TNFR2 signaling on immune cells promotes resolution of allergic and sustains long-term unresponsiveness to antigens. This regulatory function ensures immune , preventing while allowing adaptive responses.

Tissue Protection and Homeostasis

TNFR2 plays a critical role in endothelial function by promoting angiogenesis and maintaining vascular integrity, particularly in response to ischemic conditions. In endothelial cells, TNFR2 activation upregulates survival and migration pathways through TRAF2-NF-κB signaling and Bmx/Etk transactivation of VEGF receptor 2, enhancing vessel maturation and perfusion recovery post-ischemia. This receptor also protects against ischemia-reperfusion injury in the myocardium by mediating STAT3, SOCS3, and VEGF expression, which limits JNK activation and inflammatory cytokine release like IL-1β, thereby improving cardiac functional recovery. Furthermore, TNFα priming of endothelial progenitor cells via TNFR2 boosts their immunosuppressive properties and pro-angiogenic capacity, supporting vascular homeostasis by suppressing T-cell activation and promoting endothelial repair without excessive inflammation. In epithelial tissues, TNFR2 supports and maintenance in both the gut and . Physiological levels of TNFα acting through TNFR2 enhance intestinal epithelial via Src-dependent FAK , facilitating wound closure and preserving mucosal integrity independent of proliferation or . During colitis-induced injury, upregulated TNFR2 in colonic terminates excessive regenerative signaling, such as Ly6a-mediated hyperproliferation, to promote healing and restore secretory cell differentiation essential for barrier repair. In the , TNFR2 signaling in confers anti- protection against , reducing infiltration and supporting tissue during injury. TNFR2 contributes to neuronal support through neuroprotective signaling in glial cells, aiding during development and . In , TNFR2 activation promotes myelin regeneration via induction, counteracting . Microglial TNFR2 similarly modulates inflammatory responses post-central nervous system , enhancing through of immune signaling. These glial mechanisms support neuronal survival and cerebrovascular maturation, as seen in Hmgb1-mediated . In metabolic regulation, TNFR2 modulates insulin sensitivity in adipocytes by reflecting TNFα activity and influencing pro-inflammatory pathways. Elevated soluble TNFR2 levels correlate positively with (HOMA-IR), independent of adiposity, through interactions with adipokines like and that alter lipid flux and in . This signaling prevents excessive inflammation by balancing TNFα effects, though TNFR2's role is less dominant than TNFR1 in directly impairing insulin pathways, contributing to overall metabolic homeostasis in .

Protein Interactions

Key Binding Partners

Tumor necrosis factor receptor 2 (TNFR2) primarily interacts with intracellular adaptor proteins from the receptor-associated factor (TRAF) family to initiate signaling. The key adaptor is TRAF2, which binds directly to the intracellular tail of TNFR2 via a conserved PXQXT motif, enabling recruitment and activation of downstream pathways such as . TRAF2 is essential for TNFR2-mediated activation and plays a central role in promoting cell survival and proliferation. TRAF1 and TRAF3 also bind directly to TNFR2 via similar motifs; TRAF1 forms heterodimers with TRAF2 to enhance survival signaling, while TRAF3 contributes to non-canonical activation. Members of the inhibitor of apoptosis protein (IAP) family, specifically cIAP1 and cIAP2, are recruited to TNFR2 indirectly through their association with TRAF2. These proteins function as E3 ubiquitin ligases, adding K63-linked ubiquitin chains to signaling components, which amplifies NF-κB signaling and enhances signal transduction efficiency. This ubiquitination activity is critical for the non-degradative modification that sustains TNFR2-dependent cellular responses. TNFR2 signaling also involves indirect interactions with IKKγ (also known as NEMO), which is part of the IKK complex recruited via TRAF2 to facilitate canonical activation. NEMO recognizes polyubiquitin chains generated by TRAF2 and cIAPs, thereby linking TNFR2 to the kinase complex that phosphorylates IκB for its degradation. Additionally, TNFR2 exhibits potential cross-talk with TNFR1 through shared ligands like TNF-α, but maintains distinct binding partners that prevent overlap in primary signaling complexes. As a soluble modulator, TNF-α-converting enzyme (TACE), also known as ADAM17, interacts with the extracellular domain of TNFR2 to cleave and release its ectodomain, generating a soluble form that regulates ligand availability and attenuates membrane-bound signaling. This shedding mechanism helps fine-tune TNFR2 activity in response to inflammatory cues.

Signaling Complex Assembly

Upon ligand binding, tumor necrosis factor receptor 2 (TNFR2) assembles into a primary signaling complex as a homotrimer bound to trimeric TNF-α, recruiting tumor necrosis factor receptor-associated factor 2 (TRAF2) and cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) to its intracellular domains via conserved TRAF-binding motifs. This TRAF2-cIAP1/2 platform facilitates non-canonical NF-κB activation by stabilizing NIK through reduced ubiquitination and degradation, while cIAP1/2 mediate K63-linked ubiquitination on TRAF2 lysine residues, creating docking sites for the TAK1 kinase complex to propagate downstream signals. The assembly occurs rapidly post-ligand engagement, with TRAF2 binding directly to the receptor's cytoplasmic tail, followed by cIAP recruitment that enhances complex stability without involving death domain adaptors like TRADD, distinguishing it from TNFR1 complexes. Heterocomplexes form when TNFR2 associates with TNFR1 in trans, often via membrane-bound TNF on adjacent cells, enabling cooperative signaling that modulates pro-survival outcomes such as enhanced and MAPK activation. This interaction depletes shared adaptors like TRAF2 from TNFR1 complexes, shifting TNFR1 toward pro-apoptotic signaling while amplifying TNFR2-mediated cytoprotection. Localization to lipid rafts further potentiates these heterocomplexes, concentrating TNFR2 and associated TRAF2 in cholesterol-enriched domains to boost MAPK pathway activation, including JNK and p38, essential for inflammatory and proliferative responses. Complex assembly is dynamically regulated by post-translational modifications, including of TRAF2 by kinases like PKC, which fine-tunes IKK recruitment and signal duration. Disassembly is controlled by deubiquitinases such as CYLD, which removes K63-linked chains from TRAF2 and receptor-proximal components, terminating signaling and preventing excessive . These regulatory steps ensure transient complex formation, with promoting assembly and deubiquitination facilitating rapid turnover. Soluble variants of TNFR2, generated by proteolytic shedding or , form non-signaling complexes that act as decoys, binding free TNF-α trimers with high affinity to sequester and inhibit membrane TNFR activation without intracellular transduction. These soluble TNFR2 (sTNFR2) complexes circulate systemically, modulating TNF and contributing to immune by neutralizing soluble TNF while sparing membrane-bound forms that preferentially activate TNFR2.

Clinical Relevance

Neurological Disorders

In schizophrenia, elevated levels of soluble TNFR2 in serum have been observed, correlating with greater symptom severity as measured by clinical scales such as the . Genetic variants in the TNFRSF1B gene encoding TNFR2, such as the rs1061622 polymorphism, are associated with increased susceptibility to , potentially through altered inflammatory responses in the . TNFR2 plays a protective role in neuroinflammation, as demonstrated in experimental models of where selective agonism of TNFR2 reduces demyelination, limits excessive microglial activation, and attenuates proinflammatory release in the brain. In , TNFR2 exhibits a dual function: while chronic activation can contribute to pro-amyloidogenic processes and synaptic potentiation deficits in hippocampal neurons of disease models, targeted TNFR2 stimulation decreases amyloid-β production rates and mitigates neuropathological features like plaque burden. During ischemic stroke, TNFR2 deficiency, particularly in , exacerbates outcomes in preclinical models, leading to larger infarct volumes, heightened , and worsened motor and cognitive recovery, especially in females. Conversely, TNFR2 enhances neuronal survival post-stroke by promoting antioxidative mechanisms, including the activation of the Nrf2 pathway to counteract and support tissue repair. Recent investigations as of highlight TNFR2's role in hippocampal function, where astroglial TNFR2 signaling regulates in a sex-dependent manner, potentially relevant to neuropsychiatric conditions. This modulation underscores TNFR2's neuroprotective potential in mitigating symptoms linked to central imbalances.

Cancer

Tumor necrosis factor receptor 2 (TNFR2) is frequently overexpressed in various solid tumors, including , colon, cervical, and renal cancers, where it contributes to oncogenic signaling. In , elevated TNFR2 expression correlates with larger tumor size and advanced clinical stage, promoting cell survival and resistance to . Similarly, in colon cancer, TNFR2 overexpression enhances tumor and colony formation through activation of the PI3K/AKT pathway. In cervical and renal cancers, TNFR2 is expressed on malignant cells, facilitating survival signals that support tumor progression. A key mechanism underlying this pro-tumorigenic effect involves TNFR2-mediated activation of the non-canonical pathway, which drives proliferation and inhibits in tumor cells across multiple solid malignancies. Within the tumor microenvironment, TNFR2 exacerbates immune evasion by enhancing regulatory T cell (Treg) infiltration and promoting M2-like polarization of tumor-associated macrophages (TAMs). TNFR2 expression on Tregs sustains their immunosuppressive function, leading to increased tumor-infiltrating Tregs that suppress anti-tumor CD8+ T cell responses, as observed in pancreatic ductal adenocarcinoma and colorectal cancer models. Concurrently, TNFR2 signaling in macrophages induces M2 polarization, characterized by elevated IL-10 production and reduced pro-inflammatory cytokine release, further dampening immune surveillance. This dual action fosters an immunosuppressive niche conducive to tumor growth. Additionally, TNFR2 on endothelial cells activates pathways that promote metastasis by enhancing vascular permeability and adhesion molecule expression, facilitating tumor cell extravasation in breast and colorectal cancers. TNFR2 also drives angiogenesis by upregulating (VEGF) and matrix metalloproteinases (MMPs) in the stromal compartment. Activation of TNFR2 in stromal cells, including fibroblasts and endothelial cells, induces VEGF expression via HIF-1α stabilization and signaling, promoting neovascularization essential for nutrient supply in hypoxic tumors. MMPs, such as MMP-9, are similarly elevated through TNFR2-dependent pathways, enabling remodeling to support vessel sprouting in colorectal and breast cancers. High TNFR2 expression serves as a negative prognostic indicator in solid tumors, correlating with reduced overall survival and poorer outcomes in patients with breast, colorectal, and renal cancers. Meta-analyses across multiple cohorts confirm that elevated TNFR2 levels in tumor tissues or serum predict advanced stages and increased recurrence risk. In contrast, TNFR2 does not exhibit a prominent pro-tumorigenic role in hematological cancers, where its signaling more often sensitizes malignant cells to apoptosis-inducing therapies.

Autoimmune Diseases

Tumor necrosis factor receptor 2 (TNFR2) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), where genetic variations in its , TNFRSF1B, influence susceptibility. Specifically, the 196R polymorphism of TNFRSF1B is associated with increased risk of SLE in Japanese populations, with a frequency of 37% in patients compared to 18.8% in healthy controls. Additionally, elevated levels of soluble TNFR2 (sTNFR2) serve as a for activity and renal involvement in SLE, correlating with progression and long-term outcomes. In (RA), TNFR2 expressed on synovial fibroblasts contributes to the amplification of by promoting proinflammatory gene expression through pathways like , exacerbating joint damage during active disease phases. Conversely, TNFR2 signaling on regulatory T cells (Tregs) exerts protective effects by enhancing Treg expansion and suppressive function, aiding in the resolution of in later stages. TNFR2 also plays a role in other autoimmune conditions, such as (IBD), where it disrupts gut homeostasis by altering colonic epithelial cell function and barrier integrity, thereby promoting chronic inflammation. In osteoarthritis, TNFRSF1B mediates TNF-α-induced inhibition of chondrogenic differentiation in stem cells via and OPA1 upregulation, contributing to degradation through the TNF pathway. Overall, TNFR2 exhibits a dual nature in autoimmune diseases, driving pro-inflammatory responses in early or acute phases while supporting regulatory mechanisms, such as Treg-mediated suppression, during chronic stages to maintain immune balance.

Therapeutic Strategies

Therapeutic strategies targeting tumor necrosis factor receptor 2 (TNFR2) focus on modulating its signaling to address diseases where it plays a dual role in inflammation and immune regulation. Antagonists and agonists represent the primary approaches, with small molecules emerging as complementary options to fine-tune TNFR2 activity. These interventions aim to exploit TNFR2's context-specific effects, such as promoting regulatory T cell (Treg) expansion in autoimmunity or inhibiting tumor-supportive functions in cancer, while navigating challenges like off-target impacts on related pathways. Antagonists, including monoclonal antibodies, block TNFR2 to disrupt its pro-tumorigenic or immunosuppressive effects, particularly in . For instance, BI-1808, a human IgG1 monoclonal antibody that prevents TNF-α binding to TNFR2, has advanced to phase 1/2a trials for advanced solid tumors, demonstrating safety and preliminary efficacy when combined with (NCT04752826). Preclinical studies with other anti-TNFR2 monoclonal antibodies have shown inhibition of Treg proliferation and cell growth, highlighting their potential in depleting tumor-associated Tregs. Soluble TNFR2-Fc fusion proteins, such as variants of , sequester TNF ligands to indirectly antagonize TNFR2 signaling and have been explored in inflammatory models, though their broader effects on TNFR1 limit TNFR2 specificity. Agonists selectively activate TNFR2 to enhance protective functions, such as in neurological disorders and Treg expansion in autoimmune conditions. In cancer, TNFR2 agonists like BI-1910 have entered phase 1 trials for solid tumors, either alone or with , with 2025 data indicating tolerability and immune modulation (NCT06205706), with Phase 1 data presented at SITC 2025 showing tolerability and immune modulation across a wide dose range (4-900 mg Q3W) as of November 2025. Similarly, HFB200301, a first-in-class TNFR2 agonist, completed phase 1 dosing in advanced solid tumors, showing promising (NCT05238883). For autoimmunity, TRB-061, a novel TNFR2 agonist, completed IND-enabling studies by late 2024 and initiated first-in-human trials in early 2025 for inflammatory diseases, targeting Treg-mediated . In preclinical models of , TNFR2 agonism promoted differentiation and reduced inflammation, supporting its neuroprotective potential. Small molecules offer targeted modulation of TNFR2 downstream signaling or processing. TRAF2 inhibitors disrupt TNFR2-mediated survival signals, with preclinical compounds showing potential to enhance in cancer cells by blocking activation, though no phase trials were reported as of 2025. ADAM17 modulators, which regulate TNFR2 ectodomain shedding to control membrane-bound receptor levels, have been investigated for (IBD) in preclinical models; inhibition preserves membrane TNFR2 for anti-inflammatory effects. Key challenges in TNFR2 therapeutics include its context-dependent effects, where may suppress immunity in cancer but exacerbate it in , necessitating disease-specific dosing. Combination strategies, such as pairing TNFR2 agonists with anti-TNF therapies or inhibitors, are under exploration to mitigate these issues, as seen in ongoing trials for solid tumors (e.g., NCT06205706). As of 2025, phase 1/2 trials for systemic lupus erythematosus (SLE) incorporating TNFR2 for Treg expansion remain preclinical or early-stage, with no dedicated NCT identifiers reported, while cancer trials continue to advance.
Therapeutic AgentTypeTarget DiseaseTrial Phase/Status (as of 2025)NCT Identifier
BI-1808 mAbSolid tumorsPhase 1/2a, recruitingNCT04752826
BI-1910Agonist mAbSolid tumorsPhase 1, data presentedNCT06205706
HFB200301Agonist mAbAdvanced solidsPhase 1, completed dosingNCT05238883
TRB-061AgonistInflammatory diseasesPhase 1, initiated early 2025N/A (IND-enabling complete)

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