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TIGIT
TIGIT
TIGIT
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TIGIT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTIGIT, VSIG9, VSTM3, WUCAM, T-cell immunoreceptor with Ig and ITIM domains, T cell immunoreceptor with Ig and ITIM domains
External IDsOMIM: 612859; MGI: 3642260; HomoloGene: 18358; GeneCards: TIGIT; OMA:TIGIT - orthologs
Orthologs
SpeciesHumanMouse
Entrez

201633

100043314

Ensembl

ENSG00000181847

ENSMUSG00000071552

UniProt

Q495A1

P86176

RefSeq (mRNA)

NM_173799

NM_001146325

RefSeq (protein)

NP_776160

NP_001139797

Location (UCSC)Chr 3: 114.28 – 114.31 MbChr 16: 43.47 – 43.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

TIGIT (/ˈtɪdʒɪt/ TIJ-it;[5] also called T cell immunoreceptor with Ig and ITIM domains) is an immune receptor present on some T cells and natural killer cells (NK).[6] It is also identified as WUCAM[7] and Vstm3.[8] TIGIT could bind to CD155 (PVR) on dendritic cells (DCs), macrophages, etc. with high affinity, and also to CD112 (PVRL2) with lower affinity.[6]

Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients.[9] Mechanistically, research has shown that TIGIT-Fc fusion protein could interact with PVR on dendritic cells and increase its IL-10 secretion level/decrease its IL-12 secretion level under LPS stimulation, and also inhibit T cell activation in vivo.[6] TIGIT's inhibition of NK cytotoxicity can be blocked by antibodies against its interaction with PVR and the activity is directed through its ITIM domain.[10]

Clinical significance

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TIGIT regulates T-cell mediated immunity via the CD226/TIGIT-PVR pathway.[11]

HIV

[edit]

During Human Immunodeficiency Virus (HIV) infection, TIGIT expressing CD8+ T cells have been shown to be expanded and associated with clinical markers of HIV disease progression in a diverse group of HIV infected individuals.[12] Elevated TIGIT levels remained sustained even among those with undetectable viral loads. A large fraction of HIV-specific CD8+ T cells simultaneously express both TIGIT and another negative checkpoint receptor, Programmed Death Protein 1 (PD-1) and retained several features of exhausted T cells.[12] Blocking these pathways with novel targeted monoclonal antibodies synergistically rejuvenated HIV-specific CD8+ T cell responses.[12] Further, the TIGIT pathway is active in the rhesus macaque non-human primate model, and mimics expression and function during Simian Immunodeficiency Virus (SIV) infection.[12] This pathway can potentially be targeted to enhance killing of HIV infected cells during "Shock and Kill" HIV curative approaches.[13]

Cancer

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TIGIT and PD-1 has been shown to be over-expressed on tumor antigen-specific (TA-specific) CD8+ T cells and CD8+ tumor infiltrating lymphocytes (TILs) from individuals with melanoma.[14] Blockade of TIGIT and PD-1 led to increased cell proliferation, cytokine production, and degranulation of TA-specific CD8+ T cells and TIL CD8+ T cells.[14] It can be considered an immune checkpoint.[11] Co-blockade of TIGIT and PD-1 pathways elicits tumor rejection in preclinical murine models.[15] Numerous anti-TIGIT therapies have entered clinical development.

Tiragolumab

[edit]
Main article: Tiragolumab

Tiragolumab is the furthest progressed anti-TIGIT therapy in development. In non-small cell lung cancer (NSCLC) setting, the phase II CITYSCAPE clinical trial (NCT03563716) evaluated the combination of the anti-TIGIT antibody tiragolumab in combination with the anti-PD-L1 antibody atezolizumab in patients with newly-diagnosed non-small cell lung cancer whose tumors expressed PD-L1. After a median follow-up of 16.3 months, the combination of tiragolumab and atezolizumab reduced the risk of disease progression or death by 38% compared to atezolizumab monotherapy. In a subset of patients with high PD-L1 expression (at least 50% of tumor cells expressing PD-L1), the combination of tiragolumab with atezolizumab further reduced the risk of disease progression or death by 71% compared to atezolizumab monotherapy. Overall, patients who received the combination of atezolizumab and tiragolumab lived a median of 23.2 months, compared to 14.5 months with atezolizumab monotherapy.[16] Despite this initial success, there was concern that the benefit of PFS in the tiragolumab + atezolizumab arm was driven by the underperformance of atezolizumab in this trial.[17] Another concern was that there was no link between TIGIT expression and the efficacy of tiragolumab in the trial.[18]

The phase III, randomized, double-blinded SKYSCRAPER-01 trial, which evaluates the efficacy of the combination of tiragolumab and atezolizumab in NSCLC patients whose tumors have high PD-L1 expression, failed to show a significant PFS improvement in the combination arm compared with placebo + atezolizumab, although it showed "a numerical improvement" in both endpoints of PFS and overall survival (OS).[19] In August 2023, an internal PowerPoint presentation detailing OS data of the second analysis was mistakenly made public on the Internet and showed a numerical improvement in terms of OS [estimated overall survival after a median follow-up of 15,5 months: 22,9 months in tiragolumab + atezolizumab arm versus 16,7 months in placebo + atezolizumab arm, HR: 0,81 (95% CI: 0,63, 1,03)].[20] No new safety signals were identified and the trial remains blinded to investigators and patients.[21]

Tiragolumab also shows encouraging efficacy in hepatocellular carcinoma setting. In the MORPHEUS-liver trial, tiragolumab + atezolizumab + bevacizumab significantly improved response rate and PFS in both patients with positive PD-L1 expression and with negative PD-L1 expression.[22]

In small-cell lung cancer, tiragolumab didn't show any OS and PFS benefit in the SKYSCRAPER-02 trial,[23] but its development in SCLC setting is being continued as consolidation therapy for patients with limited-stage SCLC who have not progressed during/after chemotherapy and radiotherapy (NCT04308785).

In the Skyscraper-04 trial assessing the efficacy and safety of tiragolumab in patients who have recurrent, PD-L1 positive cervical cancer, the combination of tiragolumab and atezolizumab, although improved response rate in both PD-L1 low and PD-L1 high subgroups, only did so marginally and non-significantly.[24]

The combination of tiragolumab, atezolizumab, and platinum-containing chemotherapy improved PFS and OS compared with comparator arms in esophageal cancer patients in the phase II MORPHEUS-EC trial and the phase III SKYSCRAPER-08 trial.[25][26]

The Skyscraper-06 trial was ended in July 2024 in metastatic non-squamous non-small cell lung cancer as tiragolumab plus Tecentriq and chemotherapy did not meet the primary endpoints of progression-free survival (PFS) at primary analysis and overall survival (OS) at the first interim analysis.[27] The OS hazard ratio was 1.33 at the first interim analysis, indicating that patients are living longer on Keytruda than tiragolumab.[28]

See also

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References

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Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

TIGIT

View on Grokipedia
from Grokipedia
TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domains) is a co-inhibitory receptor belonging to the receptor (PVR)-like family of the , which plays a key role in modulating immune responses by suppressing T cell activation, natural killer (NK) cell cytotoxicity, and promoting (Treg) function. Discovered in through independent studies identifying it as an inhibitory molecule on lymphocytes (also known as Vsig9, Vstm3, or WUCAM), TIGIT features a single extracellular immunoglobulin variable (IgV)-like domain, a transmembrane region, and an intracellular tail containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an ITIM-like motif. It is expressed on activated T cells (including + effector, memory, follicular helper, and NKT cells), NK cells (constitutively in humans and inducibly in mice), Tregs, and , often co-expressed with other checkpoints like PD-1. TIGIT exerts its inhibitory effects primarily through binding to nectin-like ligands such as (PVR, with high affinity) and CD112 (PVRL2), which are expressed on antigen-presenting cells, tumor cells, and endothelial cells; this interaction competes with the co-stimulatory receptor CD226 (DNAM-1) for ligand binding, thereby disrupting downstream signaling pathways like PI3K and MAPK in T and NK cells. Upon ligation, TIGIT's ITIM motif recruits phosphatases such as SHIP-1 and SHP-1/2, inhibiting TCR-mediated activation, production, and granule , while also inducing tolerogenic dendritic cells via IL-10 and enhancing Treg suppression through factors like Fgl2. In addition to and CD112, TIGIT can interact with CD114 (low affinity, human-specific) and microbial proteins like nucleatum's Fap2, broadening its role in infection and inflammation control. In physiological contexts, TIGIT maintains immune by limiting excessive responses during viral infections, , and tissue repair, such as suppressing Th1/Th17-driven in models of experimental autoimmune (EAE) and . However, its upregulation on exhausted T cells in chronic settings contributes to immune evasion in tumors, correlating with poor prognosis in cancers like , non-small cell (NSCLC), and hematologic malignancies. Therapeutically, TIGIT blockade with monoclonal antibodies has shown initial promise in early trials, particularly in combination with PD-1/ inhibitors; for instance, the phase II trial demonstrated doubled objective response rates (31.3% vs. 16.2%) in PD-L1-positive NSCLC with tiragolumab plus . However, subsequent phase III trials such as SKYSCRAPER-01 did not meet primary endpoints for progression-free and overall survival as reported in 2025, leading to termination of several TIGIT programs including those for tiragolumab and vibostolimab; nonetheless, other agents like domvanalimab have shown encouraging phase II results, such as improved overall survival in gastric cancer, with additional trials ongoing as of 2025. These developments highlight TIGIT as a potential target, distinct from LAG-3 and TIM-3 due to its broader cellular expression and generally comparable immune-related adverse event profile.

Discovery and structure

Discovery

TIGIT was identified in 2009 through bioinformatics screening of immune cell transcripts as a novel member of the receptor (PVR)/nectin family of proteins. In a seminal study, Yu et al. cloned the from a and characterized it as an inhibitory receptor expressed on regulatory T cells, memory T cells, and activated conventional T cells, but absent on naive T cells. The , symbolized TIGIT, is located on human chromosome 3q13.31 and encodes a protein named T-cell immunoreceptor with Ig and ITIM domains, reflecting its single extracellular immunoglobulin-like domain and one intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) and one ITT-like motif. Initial functional studies demonstrated TIGIT's role as a co-inhibitory receptor on both T cells and natural killer (NK) cells, where it binds and nectin-2 (CD112) to suppress immune responses. Unlike PD-1, which engages B7 family ligands to inhibit T cell signaling primarily through phosphatase recruitment, TIGIT exerts its effects by promoting the generation of immunoregulatory dendritic cells that produce high levels of IL-10 while reducing IL-12, thereby dampening T cell activation and proliferation. Independent reports from the same year, including Stanietsky et al. and Levin et al., confirmed TIGIT's expression on NK cells and its direct inhibition of NK via ITIM-mediated signaling. These early findings established TIGIT as a distinct capable of modulating both adaptive and innate immunity, with subsequent work in TIGIT-deficient mice revealing enhanced T cell hyperproliferation and , underscoring its physiological role in immune suppression.

Gene and protein structure

The is located on human 3q13.31 and spans approximately 33 kb, consisting of 5 exons that encode a of 244 . The TIGIT protein is a type I transmembrane characterized by three main structural domains: an extracellular V-type immunoglobulin (IgV) domain spanning residues 1–125, a short transmembrane region from residues 126–146, and a cytoplasmic tail encompassing residues 147–244. The cytoplasmic tail features an immunoreceptor -based inhibitory motif (ITIM) at 231 (Y231) and an immunoglobulin tail (ITT)-like motif at 225 (Y225), which are critical for mediating inhibitory signaling upon . Key structural features of TIGIT include a conserved bond within the IgV domain that stabilizes its β-sandwich fold, as revealed by crystallographic studies of the extracellular region. Additionally, the protein contains N-linked sites in the extracellular domain, such as at 32 and 101, which modulate its conformation and affinity for . TIGIT belongs to the poliovirus receptor (PVR)-like family within the , sharing approximately 20–30% sequence identity with family members CD96 and CD226, particularly in the extracellular IgV domains that facilitate similar recognition motifs.

Expression and regulation

Cellular expression

TIGIT, or T-cell immunoreceptor with Ig and ITIM domains, is predominantly expressed on subsets of activated T cells and natural killer (NK) cells within the . Specifically, it is found on activated CD4+ T cells, CD8+ T cells, regulatory T cells (Tregs), follicular T helper (Tfh) cells, and γδ T cells, as well as on NK cells. TIGIT is constitutively expressed on human NK cells but inducibly upon activation in mice. Expression levels are low or absent on naive T cells, B cells, and most dendritic cells, highlighting its association with adaptive immune activation rather than resting or innate antigen-presenting states. In pathological contexts, TIGIT expression is upregulated at sites of chronic immune challenge. It is highly expressed on (TILs) across various cancers, including , non-small cell , and , as well as in chronic infection sites such as -infected lymph nodes. Elevated TIGIT is also observed in the peripheral blood of patients with cancer or , reflecting systemic immune dysregulation. Quantitative analyses reveal significant co-expression patterns and frequency variations among TIGIT-positive cells. Over 70% of TIGIT-expressing cells co-express PD-1, particularly on exhausted + T cells in tumor microenvironments, with more than 90% of PD-1-positive cells also bearing TIGIT. Additionally, TIGIT frequency is higher on Tregs (approximately 72% positive) compared to effector T cells like + T cells (around 53% positive), underscoring its preferential role in regulatory subsets.

Regulation of expression

TIGIT expression is primarily regulated at the transcriptional level during immune cell activation. Cytokines such as IL-15 upregulate TIGIT on NK cells and + T cells, particularly in response to persistent antigenic stimulation or viral infections like . Transcription factors play a central role in this process; for instance, Blimp-1 directly binds to the TIGIT promoter to enhance its expression in activated T cells, contributing to inhibitory phenotypes in chronic settings. Similarly, IL-27-induced factors c-Maf and Blimp-1 drive TIGIT transcription in T cells, linking signaling to co-inhibitory receptor upregulation. Epigenetic mechanisms further fine-tune TIGIT levels, with at the promoter region serving as a key control point. In naive or resting cells, hypermethylation suppresses TIGIT expression, while chronic stimulation leads to promoter demethylation, facilitating increased transcription, especially in regulatory T cells where this allows binding and stable expression. MicroRNAs also contribute to post-transcriptional repression; for example, miR-379-5p targets TIGIT mRNA, attenuating exhaustion in + T cells. Environmental factors in the (TME) promote TIGIT induction to foster immune suppression. Hypoxia within the TME activates pathways that upregulate exhaustion markers like TIGIT on , often in concert with HIF-1α stabilization, though direct mechanistic links require further elucidation. TGF-β, abundant in the TME, indirectly enhances TIGIT by driving T cell exhaustion and regulatory phenotypes, amplifying inhibitory receptor expression on + T cells and Tregs. Feedback loops involving TIGIT signaling maintain its expression through ITIM-mediated inhibitory pathways. Ligation of TIGIT recruits phosphatases like SHP-1 and SHP-2, suppressing activating signals that could otherwise limit inhibitory receptor upregulation, thereby autoregulating TIGIT levels in a self-reinforcing manner during prolonged immune challenges. This ITIM-dependent suppression also promotes Treg stability and IL-10 production, indirectly sustaining TIGIT expression in immunosuppressive environments.

Ligands and signaling

Ligands

TIGIT, a member of the , primarily interacts with ligands from the nectin and nectin-like (Necl) family, which are expressed on various immune and tumor cells. The principal ligand is (also known as PVR or Necl-5), to which TIGIT binds with high affinity (Kd ≈ 1–3 nM), enabling potent inhibitory signaling upon engagement. TIGIT also binds CD112 (nectin-2 or PVRL2) with substantially lower affinity (Kd ≈ 3–6 μM), contributing to its regulatory role in immune responses, though this interaction is weaker and less dominant than with . TIGIT binds CD113 (nectin-3 or PVRL3) with low affinity, though early binding assays showed conflicting or undetectable interactions. More recently, nectin-4 (PVRL4) has been identified as another ligand for TIGIT, with binding affinity approaching that of (Kd ≈ 3 nM), potentially expanding TIGIT's inhibitory network in contexts like tumor microenvironments where nectin-4 is overexpressed. Beyond mammalian ligands, TIGIT serves as a target for microbial evasion strategies. The Fap2 adhesin protein on , a bacterium associated with and other infections, directly binds TIGIT on human NK and T cells. This interaction inhibits and production, allowing the pathogen to suppress immune clearance and promote tumor progression. Recent structural studies (2025) have revealed the molecular interface of Fap2-TIGIT binding, confirming its role in pathogen-mediated inhibition. A key aspect of TIGIT's function involves competitive binding with activating receptors. TIGIT shares ligands and CD112 with the costimulatory receptor CD226 (DNAM-1) but outcompetes it due to 10- to 100-fold higher affinity, thereby displacing CD226 and shifting the balance toward immune inhibition. This competition is central to TIGIT's role in fine-tuning immune activation, particularly in exhausted or . The structural basis for these interactions resides in TIGIT's single extracellular immunoglobulin variable-like (IgV) domain, which forms a β-sandwich fold that engages ligands via their corresponding IgV domains in a lock-and-key manner. Crystal structures reveal that the binding interface buries approximately 1,600 Ų and involves conserved motifs such as the AX₆G loop and T(F/Y)P motif, with critical contacts at residues like Tyr113 in TIGIT interfacing with Phe128 in . Specific residues in the IgV domain, including Phe30 and Tyr67, contribute to the ligand interface by stabilizing hydrophobic and hydrogen-bonding interactions, underscoring the molecular precision of TIGIT's inhibitory engagement.

Downstream signaling

Upon ligation of TIGIT by its ligands, such as , the receptor's cytoplasmic tail undergoes at specific residues, including Tyr225 in the immunoglobulin tail (ITT)-like motif and Tyr233 in the inhibitory (ITIM) motif, without possessing any intrinsic enzymatic activity. TIGIT relies on adapter proteins for ; for instance, at Tyr225 in the ITT-like motif recruits the adapter protein , which in turn binds and activates the inositol phosphatase SHIP-1. Similarly, the ITIM motif at Tyr233 facilitates recruitment of the tyrosine phosphatases SHP-1 and SHP-2 upon . These recruited phosphatases initiate inhibitory signaling cascades in immune cells. The primary downstream effects involve suppression of key activation pathways. SHIP-1 dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), thereby inhibiting the PI3K/Akt signaling axis, which is critical for cell survival, proliferation, and cytokine production. Concurrently, SHP-1 and SHP-2 dephosphorylate substrates in the MAPK/ERK pathway, attenuating ERK activation and downstream transcription factors that drive inflammatory responses. These mechanisms collectively dampen immune cell activation without directly altering the receptor's kinase-independent nature. TIGIT signaling further promotes suppression through indirect modulation of co-stimulatory molecules and production. In T cells, TIGIT ligation enhances the of the activating receptor CD226 (DNAM-1) via recruited phosphatases, thereby blocking CD226-mediated and T cell . In regulatory T cells (Tregs), of TIGIT induces the expression and secretion of immunosuppressive factors, including interleukin-10 (IL-10) and fibrinogen-like protein 2 (FGL2), which amplify Treg suppressive function and inhibit pro-inflammatory Th1 and Th17 responses. TIGIT exhibits synergistic crosstalk with other inhibitory checkpoints, notably PD-1, to enhance overall suppression. Both receptors recruit overlapping phosphatases (SHP-1/2), leading to converged inhibition of shared downstream targets like CD226, where dual signaling amplifies and blocks co-stimulatory signals more effectively than either pathway alone. This interaction underscores TIGIT's role in fine-tuning immune inhibition through coordinated phosphatase activity.

Functions in immune cells

In T cells

TIGIT serves as a key inhibitory receptor on effector T cells, where it suppresses their activation and function through both competitive and direct signaling mechanisms. On CD8+ and CD4+ effector T cells, TIGIT competes with the activating receptor CD226 for binding to shared ligands such as and CD112, leading to cis displacement of CD226 from the immune synapse and thereby preventing costimulatory signaling. Additionally, TIGIT engages direct inhibitory signaling via its intracellular ITIM and ITT motifs, which recruit phosphatases like SHIP-1 and SHP-1/2 to dampen proximal T cell receptor signals. This dual inhibition results in reduced proliferation, diminished cytokine production including IFN-γ and IL-2, and impaired cytotoxic granule release in effector T cells upon antigen stimulation. In regulatory T cells (Tregs), TIGIT expression enhances their immunosuppressive capacity, promoting by selectively targeting proinflammatory responses. TIGIT+ Tregs exhibit heightened suppressive activity through increased secretion of the IL-10 and fibrinogen-like protein 2 (Fgl2), which collectively inhibit maturation and proinflammatory production such as IL-12 and IL-23. Furthermore, TIGIT signaling in Tregs induces metabolic shifts, including inhibition of and reduced glucose uptake, which favor and sustain long-term suppressive function in tolerogenic environments. These effects preferentially suppress Th1 and Th17 differentiation while sparing Th2 responses, thereby maintaining a balanced immune homeostasis. TIGIT is a prominent marker of T cell exhaustion in chronic immune settings, such as persistent infections or tumors, where it identifies dysfunctional T cells with limited responsiveness. Exhausted + T cells frequently co-express TIGIT with PD-1, with over 70% of TIGIT+ cells also expressing PD-1 and more than 90% of PD-1+ cells showing TIGIT co-expression, correlating strongly with anergic states and impaired effector functions. This co-expression pattern reflects advanced T cell dysfunction, as TIGIT can partially restore proliferation and secretion in these populations. Regarding T cell differentiation, TIGIT modulates lineage commitment by favoring Treg development over proinflammatory subsets. Ligation of TIGIT during T cell activation promotes induced Treg (iTreg) differentiation through enhanced expression and IL-10 production, while simultaneously repressing Th1 and Th17 programs via downregulation of T-bet and RORγt. This selective influence helps prevent excessive and supports regulatory dominance in steady-state conditions.

In NK cells and other cells

TIGIT serves as an inhibitory receptor on natural killer (NK) cells, where it suppresses key effector functions through its immunoreceptor tyrosine-based inhibitory motif (ITIM), which recruits SHIP-1 and other phosphatases to dampen activating signals. In particular, TIGIT engagement inhibits NK cell , antibody-dependent cellular cytotoxicity (), and production, including interferon-gamma (IFN-γ), thereby limiting antitumor and antiviral responses. TIGIT expression is upregulated on NK cells during chronic stimulation, contributing to their exhaustion phenotype in tumor microenvironments and persistent infections. Quantitative analyses reveal that TIGIT-positive NK cells exhibit reduced expression of perforin and compared to TIGIT-negative counterparts, correlating with diminished cytotoxic potential. Blockade of TIGIT restores NK cell-mediated ADCC and enhances their antitumor activity, as demonstrated in preclinical models where anti-TIGIT antibodies improved NK cell responses against tumor targets expressing CD155. Beyond NK cells, TIGIT exerts inhibitory effects on γδ T cells, where its expression on these innate-like lymphocytes is associated with functional exhaustion and , particularly in cancer settings, leading to reduced proliferation and secretion. In monocytes, TIGIT may promote a suppressive M2-like phenotype, as its blockade shifts monocyte-derived macrophages toward an antitumor M1 state with increased proinflammatory production. TIGIT is expressed on subsets of B cells, such as memory B cells and regulatory B cells (e.g., TIM-1+ B cells), where it contributes to immune regulation by directly inhibiting T cell activation and arresting proinflammatory functions of monocytes and dendritic cells. In dendritic cells, TIGIT expression is minimal, with no substantial impact on their effector functions reported in immune responses.

Role in diseases

Cancer

TIGIT plays a in tumor immune evasion by inhibiting the function of T cells and natural killer (NK) cells within the (TME). Through its interaction with ligands such as and CD112, TIGIT delivers inhibitory signals that suppress production, proliferation, and of these immune cells, thereby promoting T cell and NK cell exhaustion. This exhaustion is characterized by reduced antitumor activity and enhanced suppression, allowing tumors to evade immune surveillance. TIGIT is overexpressed on tumor-infiltrating lymphocytes (TILs) in various solid tumors, including , non-small cell lung cancer (NSCLC), and , as well as in hematologic malignancies such as (DLBCL). In the TME, TIGIT frequently co-exists with other immune checkpoints, notably PD-1, with studies showing that TIGIT is frequently co-expressed with PD-1 on exhausted + T cells, amplifying synergistic suppression of immune responses. This co-expression pattern underscores TIGIT's contribution to a multifaceted inhibitory network that sustains tumor progression. High TIGIT expression on TILs correlates with poor clinical outcomes across multiple cancer types. In NSCLC, , and gastric cancer, elevated TIGIT levels in TILs are associated with advanced disease stages and reduced overall survival (OS) and (PFS), as evidenced by meta-analyses reporting a of 1.42 (95% CI 1.07-1.89) for worse OS with high TIGIT. Furthermore, TIGIT serves as a potential for response to inhibitors (ICIs), where its upregulation predicts resistance to PD-1/ blockade, highlighting its prognostic and predictive utility in .

Infectious diseases

TIGIT is upregulated on exhausted CD8+ T cells and natural killer (NK) cells during human immunodeficiency virus (HIV) infection, serving as a marker of T cell dysfunction and disease progression. In chronic HIV, TIGIT expression on CD8+ T cells correlates positively with viral load and negatively with CD4+ T cell counts, with higher frequencies of TIGIT+PD-1+ CD8+ T cells observed in untreated individuals compared to elite controllers or those on antiretroviral therapy. Similarly, in simian immunodeficiency virus (SIV) infection, TIGIT marks exhausted CD8+ T cells in lymphoid tissues, correlating with viral replication. Blockade of TIGIT enhances NK cell cytotoxicity and antibody-dependent cellular cytotoxicity against autologous HIV-infected CD4+ T cells, reducing survival of latently infected reservoir cells expressing poliovirus receptor (PVR), a TIGIT ligand upregulated on infected cells. In other viral infections, TIGIT inhibits adaptive immune responses, as demonstrated in the virus (LCMV) model, where it is highly expressed on exhausted CD8+ T cells during chronic infection and limits excessive inflammation by promoting IL-10 production, thereby reducing tissue damage in organs like the liver and lungs without improving viral control. In models, TIGIT upregulation on virus-specific CD8+ T cells and NK cells contributes to impaired effector functions, mirroring HIV pathology. Microbial pathogens exploit TIGIT for immune evasion; for instance, uses agglutinin-like sequence proteins (ALS6, ALS7, ALS9) as ligands to bind TIGIT on NK and T cells, suppressing responses and promoting fungal persistence in systemic infections, as evidenced by improved survival and reduced fungal burdens in TIGIT-knockout mice. Mechanistically, TIGIT suppresses NK cell migration in HIV-infected individuals by inhibiting hypoxia-inducible factor 1-alpha (HIF-1α) expression through blockade of PI3K/AKT/mTORC1 and ERK signaling pathways, which impairs and toward infected targets. TIGIT also limits the expansion and function of adaptive NKG2C+ NK cells during infection, with elevated TIGIT levels associated with reduced frequencies of these memory-like NK cell precursors and diminished cytotoxic responses against infected cells. Clinically, TIGIT expression is higher on immune cells in chronic infections compared to acute phases; for example, in chronic , TIGIT+ + T cells are more frequent than in healthy controls, and similar patterns occur in chronic LCMV versus resolved acute infections. This upregulation persists in viral latency, such as reservoirs, where TIGIT blockade shows potential to reactivate and eliminate latent cells by restoring NK and T cell functions.

Autoimmune diseases

TIGIT plays a protective role in autoimmune diseases by limiting excessive immune responses and enhancing the suppressive function of regulatory T cells (Tregs). In experimental autoimmune (EAE), a mouse model of , TIGIT deficiency leads to increased susceptibility and more severe disease progression, characterized by heightened Th17 cell infiltration in the and elevated proinflammatory production. Similarly, TIGIT engagement on Tregs promotes selective inhibition of Th1 and Th17 responses in EAE and T cell transfer models of , thereby mitigating inflammation without broadly impairing adaptive immunity. In human autoimmune diseases, TIGIT expression is upregulated on CD4+ T cells in patients with (RA) and systemic lupus erythematosus (SLE), with correlations to disease activity that vary across studies (positive in some, negative in others) such as the SLE Disease Activity Index (SLEDAI) and levels of autoantibodies or inflammatory markers. This elevation suggests a compensatory mechanism to foster , as TIGIT+ T cells exhibit reduced proliferation and secretion despite an activated phenotype marked by higher PD-1 and expression. In , increased TIGIT+ CD4+ T cell frequencies also predict better responses to treatment, highlighting its potential as a for modulation. TIGIT exhibits a dual role in : inhibitory on effector T cells to dampen their and proinflammatory output, but agonistic on Tregs to amplify suppression through induction of IL-10 and fibrinogen-like protein 2 (FGL2). Ligation of TIGIT on Tregs upregulates FGL2 expression, which selectively targets Th1/Th17 differentiation while sparing Th2 responses, as demonstrated and . This mechanism underlies TIGIT's tolerance-promoting effects in autoimmune settings. In preclinical models, agonistic anti-TIGIT antibodies ameliorate autoimmune severity by restoring T cell balance, reducing Th17 frequencies, and decreasing CNS inflammation in EAE mice. For instance, administration of such antibodies during EAE induction significantly lowers clinical scores and proinflammatory cytokine levels, supporting TIGIT as a strategy to enhance Treg-mediated control without exacerbating .

Therapeutic targeting

Inhibitory antibodies

Inhibitory antibodies targeting TIGIT are monoclonal antibodies designed to block the interaction between TIGIT and its ligands, such as (PVR) and CD112 (PVRL2), thereby reversing TIGIT-mediated immune suppression and enhancing antitumor immune responses. These agents primarily function by preventing TIGIT from delivering inhibitory signals to T cells and natural killer (NK) cells, allowing co-stimulatory pathways like CD226 to predominate. Several such antibodies have advanced to clinical development, focusing on their ability to reinvigorate exhausted immune cells without depleting TIGIT-expressing populations. However, as of 2025, many major programs have been discontinued following phase 3 trial failures. Tiragolumab, developed by Roche, is a fully human IgG1/kappa monoclonal antibody that binds to the immunoglobulin variable (IgV) domain of TIGIT, thereby inhibiting its interaction with ligands and blocking downstream inhibitory signaling. In the phase III SKYSCRAPER-01 trial evaluating tiragolumab plus atezolizumab in patients with PD-L1-positive metastatic non-small cell lung cancer (NSCLC), the combination demonstrated a median progression-free survival (PFS) of 7.0 months compared to 5.6 months with atezolizumab alone (hazard ratio 0.78). Despite initial promise in earlier trials like CITYSCAPE, subsequent analyses revealed no overall survival benefit, leading to discontinuation of the tiragolumab program in 2025. Other notable anti-TIGIT antibodies include vibostolimab (Merck), a humanized IgG1 antibody that blocks TIGIT-ligand binding to restore T-cell activation; domvanalimab (Gilead), an Fc-silent IgG1 antibody designed to avoid antibody-dependent cellular cytotoxicity while promoting immune checkpoint reversal; and ociperlimab (BeiGene), an Fc-competent antibody that similarly disrupts TIGIT engagement with CD155 to enhance immune effector function. Development of vibostolimab and ociperlimab was discontinued in 2025 due to lack of efficacy in phase 3 trials, while domvanalimab continues in select indications. These agents are engineered as non-depleting to prioritize blockade over cell elimination, emphasizing TIGIT's role as a checkpoint rather than a depletable target. The primary mechanism of these inhibitory antibodies involves relieving TIGIT's of CD226, thereby restoring CD226-mediated co-stimulatory signaling in T cells and NK cells, which enhances and production against tumors. Preclinical studies in mouse tumor models have shown that TIGIT blockade increases CD8+ T-cell infiltration and NK-cell activity, leading to reduced tumor growth and improved survival, often synergizing with PD-1 inhibition to overcome immune exhaustion. For instance, anti-TIGIT treatment in syngeneic models upregulated and IFN-γ expression in effector cells, demonstrating potent antitumor efficacy. Safety profiles of TIGIT inhibitory antibodies have generally been favorable, with most adverse events classified as mild to moderate and manageable. Common side effects include infusion-related reactions, , and rash, occurring at low rates without significant increases in severe immune-related toxicities compared to PD-1 inhibitors alone. Clinical data from phase I/II trials indicate that doses up to 600 mg of tiragolumab or equivalent for other agents are well-tolerated, supporting their advancement in settings.

Combination therapies

Combination therapies targeting TIGIT blockade have emerged as a strategy to enhance antitumor immunity by addressing multiple immunosuppressive pathways in the , particularly given the frequent co-expression of TIGIT with PD-1 on over 70% of + tumor-infiltrating lymphocytes in various cancers, which justifies dual inhibition to overcome compensatory resistance mechanisms. This approach leverages synergistic effects, as TIGIT and PD-1 pathways converge on similar downstream signaling to inhibit T cell activation, and their combined promotes clonal expansion and effector function of antitumor + T cells more effectively than monotherapy. However, as of 2025, several major anti-TIGIT programs have been discontinued following phase 3 failures, with ongoing efforts focused on select combinations like those involving domvanalimab. Prominent combinations pair TIGIT inhibitors with PD-1/PD-L1 blockers, such as tiragolumab (anti-TIGIT) plus atezolizumab (anti-PD-L1), which showed an overall survival of 23.1 months versus 16.9 months with atezolizumab alone in PD-L1-high non-small cell lung cancer (NSCLC), though the difference was not statistically significant in the phase 3 SKYSCRAPER-01 trial. Earlier phase 2 data from the CITYSCAPE trial indicated improved progression-free survival and objective response rates with this duo in PD-L1-positive NSCLC, supporting further exploration despite mixed phase 3 outcomes. Bispecific antibodies like rilvegostomig (anti-PD-1/TIGIT) have demonstrated objective response rate improvements in phase 2 trials, with durable responses in checkpoint inhibitor-naive metastatic NSCLC regardless of PD-L1 status and favorable tolerability profiles. Beyond PD-1/PD-L1, TIGIT blockade combines with CTLA-4 or LAG-3 inhibitors to target broader T cell exhaustion signatures, as these checkpoints often co-express with TIGIT on dysfunctional tumor-reactive T cells, potentially amplifying immune activation in refractory settings. In the ARC-7 phase 2 trial for PD-L1-high NSCLC, domvanalimab (anti-TIGIT) plus zimberelimab (anti-PD-1) achieved an objective response rate of 41% compared to 27% with zimberelimab monotherapy, with similar improvements in the triplet arm adding an adenosine pathway inhibitor. Ongoing phase 3 trials with domvanalimab combinations, such as in gastric cancer, have shown promising survival data as of October 2025. Additionally, TIGIT inhibition enhances CAR-T cell therapy efficacy by reducing exhaustion markers on engineered T cells, leading to improved tumor control in preclinical models of solid tumors. Responses to these combinations are often biomarker-driven, with TIGIT-expressing tumors showing superior outcomes, as high TIGIT levels on correlate with better responses to dual blockade by indicating an exhausted but targetable T cell population. Overall, these strategies highlight the potential of multi-checkpoint inhibition to broaden and deepen antitumor responses, though challenges persist following recent discontinuations, with remaining phase 3 trials needed to confirm durable benefits across indications.

Agonistic approaches and emerging strategies

Agonistic anti-TIGIT antibodies have shown potential in treating autoimmune diseases by activating TIGIT signaling to enhance (Treg) function and suppress pathogenic immune responses. In preclinical models of (MS) and (RA), these antibodies promote Treg-mediated immunosuppression through upregulation of interleukin-10 (IL-10) and fibrinogen-like protein 2 (Fgl2), leading to reduced Th1/Th17 cell activity and decreased disease severity. For instance, an anti-human TIGIT agonistic inhibited T follicular helper (Tfh) and T peripheral helper (Tph) cells while boosting Treg expansion, resulting in ameliorated symptoms in experimental autoimmune , a model for MS. Similarly, agonistic clones modulated T cell responses , preventing autoimmunity development in susceptible models by enhancing inhibitory signaling downstream of TIGIT. Emerging strategies beyond traditional antibodies include small-molecule inhibitors targeting TIGIT-related signaling pathways. Elraglusib (9-ING-41), a selective inhibitor of (GSK-3β), reduces TIGIT expression on immune cells, thereby alleviating checkpoint-mediated suppression and enhancing + T cell cytotoxicity in preclinical cancer models. Non-antibody approaches, such as D-peptides, offer novel ways to modulate TIGIT-ligand interactions; a mirror-image phage display-derived D-peptide (DTBP-3) effectively blocks TIGIT binding to receptor (PVR), inhibiting tumor growth and in models without degradation issues common to L-peptides. In 2024, was identified as a dual modulator that disrupts TIGIT/PVR engagement while inducing in tumor cells via iron-dependent , synergizing with to boost anti-tumor immunity in preclinical settings. Modifications to chimeric antigen receptor (CAR) T cells represent another innovative strategy to counter TIGIT-mediated exhaustion. Preclinical studies in mantle cell lymphoma models demonstrate that downregulating TIGIT in CAR-T cells via short hairpin RNA prevents T cell suppression and relapse, improving long-term tumor control and progression-free survival compared to unmodified CAR-T. Dual downregulation of TIGIT and PD-1 further enhances effector and early memory phenotypes, reducing tumor burden even at low cell doses. Challenges in these approaches include the need for reliable biomarkers to predict response, such as co-expression of TIGIT and PD-1 on + T cells, which correlates with outcomes but requires validation for agonistic contexts. As of November 2025, amid discontinuations of many inhibitory TIGIT programs, research has increasingly shifted toward agonistic approaches, hematologic cancers, and combinations with existing therapies to overcome resistance, with bispecific antibodies co-targeting TIGIT and poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG) showing enhanced anti-tumor effects in early-phase trials by simultaneously blocking both checkpoints on .

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