# TIGIT: Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) Signaling and NK Cell Inhibition ## Key Takeaways - TIGIT is a type I transmembrane glycoprotein functioning as a critical immune checkpoint receptor expressed on NK cells, T cells, and Tregs, which attenuates innate and adaptive antitumor immunity by recruiting phosphatases SHP-1 and SHP-2 via its intracellular ITIM motif. - TIGIT competes with the co-stimulatory receptor CD226 for binding to shared ligands CD155 (PVR) and CD112 (nectin-2), which are often overexpressed on tumor cells and antigen-presenting cells, thereby suppressing NK cell cytotoxicity and T cell effector functions. - The human TIGIT gene is located on chromosome 3q13.31 and its promoter region is regulated by transcription factors such as PRDM1, MAF, NFAT, STATs, and HIF-1α, with enhancer elements regulated by T-bet, Eomes, and FOXP3. - Germline variants in TIGIT have been linked to susceptibility to autoimmune diseases and severe COVID-19, while somatic mutations are uncommon but can affect ligand binding, and high TIGIT expression on tumor-infiltrating lymphocytes is associated with poor prognosis in various cancers. - Multiple monoclonal antibodies targeting TIGIT, including tiragolumab, vibostolimab, and domvanalimab, are in clinical development, primarily in combination with PD-1/PD-L1 blockade, for the treatment of solid tumors. - TIGIT plays a significant role in host-pathogen interactions, with upregulation observed in HTLV-1 infection, HIV, and *Trypanosoma cruzi* infection, contributing to viral persistence and immune exhaustion. --- ## Executive Summary & Key Metadata T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a type I transmembrane glycoprotein belonging to the poliovirus receptor (PVR)/nectin family of immunoglobulin superfamily (IgSF) proteins. TIGIT functions as a critical immune checkpoint receptor expressed on the surface of natural killer (NK) cells, CD8+ and CD4+ T cells, regulatory T cells (Tregs), and subsets of innate lymphoid cells. Its primary role is to attenuate innate and adaptive antitumor immunity, limit autoimmune pathology, and regulate tissue-protective immune responses. TIGIT competes with the co-stimulatory receptor CD226 (DNAM-1) for binding to the shared ligands CD155 (PVR) and CD112 (nectin-2), which are overexpressed on tumor cells and antigen-presenting cells. Through its intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoglobulin tail tyrosine (ITT)-like motif, TIGIT recruits phosphatases such as SHP-1 and SHP-2, leading to suppression of NK cell cytotoxicity, cytokine production, and T cell effector functions. The gene encoding TIGIT is located on human chromosome 3q13.31 and is a focus of intense translational research, with multiple monoclonal antibodies (e.g., tiragolumab, vibostolimab, domvanalimab) currently in clinical development for solid tumors. | **Attribute** | **Detail** | |---|---| | HGNC Symbol | TIGIT | | UniProt Accession | Q495A1 | | Representative PDB ID | 3Q0H | | Chromosomal Locus | 3q13.31 | | Primary Molecular Function | Co-inhibitory immune checkpoint receptor; negative regulator of NK cell and T cell activation | | Disease & Pathology Associations | Cancer (NSCLC, melanoma, colorectal, pancreatic, breast, esophageal, cervical), autoimmune diseases (rheumatoid arthritis, multiple sclerosis, systemic sclerosis), viral infections (HTLV-1, HIV, SARS-CoV-2), atherosclerosis, acute kidney injury | ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Localization and Gene Structure The human TIGIT gene is located on the long arm of chromosome 3 at cytogenetic band 3q13.31, spanning approximately 12.5 kilobases of genomic DNA. The gene is oriented on the minus strand (reverse orientation) relative to the centromere-to-telomere convention. The genomic coordinates per the GRCh38/hg38 assembly are approximately chr3:114,277,000–114,289,500. The TIGIT locus resides within a genomic region enriched for immune-related genes, including the neighboring genes encoding CD96 and CD226, which also interact with the PVR family ligands. This clustering suggests a shared evolutionary origin and potential coordinated transcriptional regulation. The TIGIT gene comprises seven exons and six introns. Exon 1 encodes the 5' untranslated region (UTR) and the signal peptide. Exons 2 and 3 encode the N-terminal immunoglobulin variable (IgV)-like domain, which is the ligand-binding region. Exon 4 encodes the stalk region and the transmembrane domain. Exon 5 encodes the cytoplasmic tail containing the ITT-like motif. Exon 6 encodes the ITIM motif. Exon 7 contains the 3' UTR. The intron-exon boundaries conform to the canonical GT-AG splice donor-acceptor consensus sequences. ### 1.2 Promoter Architecture and Transcription Factor Binding The proximal promoter region of TIGIT spans approximately 1.5 kilobases upstream of the transcription start site (TSS). This region lacks a canonical TATA box but contains multiple GC-rich elements and CpG islands, characteristic of constitutively expressed or inducible immune genes. Several transcription factor binding sites have been identified through chromatin immunoprecipitation sequencing (ChIP-seq) and electrophoretic mobility shift assays (EMSA): - **PRDM1 (Blimp-1):** The transcriptional repressor PRDM1 binds to the TIGIT promoter and is a master regulator of T cell exhaustion. PRDM1 directly induces TIGIT expression in CD8+ T cells during chronic viral infection and tumor progression. - **MAF (c-MAF):** The transcription factor MAF, which is upregulated in exhausted T cells and Tregs, binds to the TIGIT promoter and drives its expression. - **NFAT (Nuclear Factor of Activated T-cells):** NFAT family members, particularly NFATc1, cooperate with AP-1 to induce TIGIT transcription upon T cell receptor (TCR) engagement. - **STAT3 and STAT5:** Signal transducer and activator of transcription proteins bind to response elements in the TIGIT promoter, linking cytokine signaling (IL-2, IL-6, [IL-10](/knowledge/bioinformatics/genes/immunology-checkpoints/il10-gene-structure-function-pathway)) to TIGIT upregulation. - **HIF-1α:** Hypoxia-inducible factor 1-alpha binds to hypoxia response elements (HREs) in the TIGIT promoter, providing a mechanistic link between the hypoxic tumor microenvironment and immune checkpoint upregulation. ### 1.3 Enhancer Elements and Chromatin Architecture Three-dimensional chromatin conformation studies using Hi-C and [ATAC-seq](/knowledge/bioinformatics/atac-seq-and-chromatin-accessibility-profiling) have identified several putative enhancer elements within the TIGIT locus. A distal enhancer located approximately 20 kilobases upstream of the TSS shows open chromatin marks (H3K27ac, H3K4me1) specifically in activated CD8+ T cells and NK cells. This enhancer contains binding sites for T-bet (TBX21) and Eomesodermin (EOMES), transcription factors that govern effector and memory T cell differentiation. A second enhancer element within intron 1 of TIGIT is bound by [FOXP3](/knowledge/bioinformatics/genes/immunology-checkpoints/foxp3-gene-structure-function-pathway) in regulatory T cells, suggesting lineage-specific regulation of TIGIT expression in Tregs. DNA methylation at CpG sites within the TIGIT promoter and gene body inversely correlates with gene expression. In melanoma, hypomethylation of specific CpG sites in the TIGIT locus is associated with increased TIGIT expression in tumor-infiltrating lymphocytes and predicts response to anti-PD-1 immunotherapy. Similarly, in uveal melanoma, TIGIT DNA methylation is associated with BAP1 mutational status and overall survival. These epigenetic regulatory mechanisms are being explored as potential companion biomarkers for anti-TIGIT therapies. ### 1.4 Alternative Splicing and Isoforms Alternative splicing of the TIGIT pre-mRNA generates multiple transcript variants. The canonical transcript (ENST00000361853.8) encodes the full-length 244-amino acid protein. A splice variant lacking exon 3 (which encodes part of the IgV domain) produces a truncated protein that is retained in the endoplasmic reticulum and does not reach the cell surface. This variant may act as a dominant-negative regulator of TIGIT signaling. A second variant with an alternative 3' splice site in exon 5 results in a protein with a shortened cytoplasmic tail lacking the ITIM motif. This isoform, if expressed, would be unable to recruit SHP-1/SHP-2 phosphatases and might function as a decoy receptor. However, the physiological relevance of these splice variants in human tissues remains incompletely characterized. [Single-cell RNA sequencing](/knowledge/bioinformatics/single-cell-rna-sequencing-from-bulk-to-resolution) studies have noted that TIGIT is often under-detected due to alignment issues with homologous genes such as PVRIG, necessitating gene model corrections for accurate quantification. ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Primary Structure and Domain Organization The human TIGIT protein (UniProt Q495A1) is a 244-amino acid type I transmembrane glycoprotein with a predicted molecular weight of approximately 26.8 kDa (unglycosylated) and 30–35 kDa (glycosylated). The protein is organized into distinct structural and functional domains from the N-terminus to the C-terminus: 1. **Signal Peptide (residues 1–21):** A hydrophobic leader sequence that directs the nascent polypeptide to the endoplasmic reticulum for co-translational translocation into the secretory pathway. The signal peptide is cleaved by signal peptidase during maturation. 2. **Immunoglobulin Variable (IgV)-like Domain (residues 22–141):** The extracellular ligand-binding domain. This domain adopts the characteristic IgV fold consisting of two antiparallel β-sheets packed against each other, with a disulfide bond between conserved cysteine residues (Cys58 and Cys122) stabilizing the structure. The IgV domain of TIGIT is structurally most similar to the corresponding domains of CD96 and CD226, reflecting their shared ligand specificity for PVR family proteins. The ligand-binding interface is formed by the C'C'' and F G loops, which contain residues critical for CD155 and CD112 recognition. 3. **Stalk Region (residues 142–161):** A flexible proline-rich linker connecting the IgV domain to the transmembrane helix. This region provides conformational flexibility that may facilitate optimal orientation of the ligand-binding domain relative to the cell membrane. 4. **Transmembrane Domain (residues 162–182):** A hydrophobic α-helix of approximately 21 amino acids that anchors the protein in the plasma membrane. The transmembrane domain contains a conserved GxxxG motif that may mediate homodimerization or heterodimerization with other receptors. 5. **Cytoplasmic Tail (residues 183–244):** The intracellular signaling domain containing two conserved signaling motifs: - **Immunoglobulin Tail Tyrosine (ITT)-like Motif (residues 203–210):** Sequence Y203-x-x-x-I207-x-x-Y210. This motif is phosphorylated by Src family kinases (e.g., LCK, FYN) upon receptor engagement. The ITT-like motif is essential for TIGIT-mediated inhibition of NK cell cytotoxicity. - **Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) (residues 231–236):** Sequence I231-x-Y233-x-x-L236. Upon tyrosine phosphorylation, this motif recruits the SH2 domain-containing protein tyrosine phosphatases SHP-1 (PTPN6) and SHP-2 (PTPN11), which dephosphorylate downstream signaling molecules. ### 2.2 Crystal Structure and Ligand Recognition The three-dimensional structure of the TIGIT IgV domain has been determined by X-ray crystallography (PDB: 3Q0H) at a resolution of 2.1 Å. The structure reveals a classic IgV fold with a β-sandwich architecture comprising nine β-strands (A, B, C, C', C'', D, E, F, G). The A strand is split into A and A' segments, and the C' and C'' strands are separated by a short loop. The ligand-binding site is located on the face formed by the C'C'' and FG loops, which form a hydrophobic groove flanked by charged residues. The crystal structure of TIGIT in complex with its primary ligand CD155 (PVR) has also been solved (PDB: 3UDW). The interaction interface buries approximately 1,500 Ų of solvent-accessible surface area and is dominated by hydrophobic contacts. Key residues at the interface include Phe107, Leu110, and Pro114 on TIGIT, which insert into a hydrophobic pocket on CD155. Electrostatic interactions between Glu60 and Arg113 on TIGIT and complementary charged residues on CD155 contribute to binding specificity. The binding affinity (Kd) of TIGIT for CD155 is approximately 0.2–0.5 μM, which is higher than the affinity of CD226 for CD155 (Kd ~1–2 μM), explaining the competitive advantage of TIGIT over CD226 at high ligand densities. TIGIT also binds CD112 (nectin-2) with lower affinity (Kd ~5–10 μM) and does not bind CD113 (nectin-3). The structural basis for this differential ligand selectivity has been mapped to residue differences in the FG loop of the IgV domain. ### 2.3 Post-Translational Modifications TIGIT undergoes several post-translational modifications that regulate its expression, trafficking, and signaling: - **N-linked Glycosylation:** The IgV domain contains two conserved N-glycosylation sites (Asn32 and Asn76). Glycosylation at these sites is required for proper protein folding, cell surface expression, and ligand binding. Altered glycosylation patterns in tumor cells may affect TIGIT-ligand interactions. - **Phosphorylation:** Tyrosine residues within the ITT-like motif (Tyr203, Tyr210) and ITIM (Tyr233) are phosphorylated upon receptor engagement. Src family kinases phosphorylate Tyr203 and Tyr210, while Tyr233 is phosphorylated by both Src kinases and possibly by receptor-associated kinases. Phosphorylation of these residues creates docking sites for SH2 domain-containing proteins. - **Palmitoylation:** Cysteine residues in the transmembrane domain and juxtamembrane region may undergo S-palmitoylation, which promotes partitioning into lipid rafts and facilitates signaling complex formation. - **Ubiquitination:** TIGIT is subject to ubiquitin-mediated degradation. The E3 ubiquitin ligase MARCH1 (membrane-associated RING-CH protein 1) has been shown to ubiquitinate TIGIT, leading to its internalization and lysosomal degradation. This mechanism may be exploited by tumor cells to modulate TIGIT surface levels. ### 2.4 Interactive 3D Visualizer [Interactive 3D Protein Visualizer: Load TIGIT (PDB: 3Q0H)](/tools/protein-structure-viewer?source=direct&pdbId=3Q0H) The interactive visualizer allows users to explore the three-dimensional structure of the TIGIT IgV domain. Key structural features to examine include: - The β-sandwich architecture of the IgV fold - The disulfide bond between Cys58 and Cys122 - The ligand-binding groove formed by the C'C'' and FG loops - Surface electrostatic potential maps showing the charged patches involved in CD155 binding - Conservation scores mapped onto the structure to identify functionally important residues ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 TIGIT Expression and Regulation TIGIT is expressed on multiple immune cell types, with expression levels varying by cell type, activation state, and tissue microenvironment: - **Natural Killer (NK) Cells:** TIGIT is constitutively expressed on the surface of resting NK cells, with higher expression on CD56^dim CD16^+ mature NK cells compared to CD56^bright immature NK cells. Activation of NK cells through cytokine stimulation (IL-2, IL-15) or engagement of activating receptors further upregulates TIGIT expression. - **CD8+ T Cells:** TIGIT is minimally expressed on naive CD8+ T cells but is rapidly upregulated following TCR stimulation. Sustained antigen exposure in chronic infections and tumors leads to high TIGIT expression on exhausted CD8+ T cells, where it co-localizes with PD-1, TIM-3, and LAG-3. - **CD4+ T Cells:** TIGIT is expressed on subsets of CD4+ T cells, particularly Th1 and Th17 cells, as well as on follicular helper T cells (Tfh). TIGIT expression on Tfh cells is regulated by B cell-derived signals. - **Regulatory T Cells (Tregs):** TIGIT is highly expressed on a subset of Foxp3+ Tregs, particularly those with a highly suppressive phenotype. TIGIT+ Tregs exhibit enhanced suppressive function and produce IL-10. - **Other Cell Types:** TIGIT is expressed on subsets of innate lymphoid cells (ILCs), mucosal-associated invariant T (MAIT) cells, and invariant NKT (iNKT) cells. Expression has also been reported on B cells and dendritic cells under certain conditions. ### 3.2 Ligand Engagement and Competitive Signaling TIGIT exerts its inhibitory function through multiple, non-mutually exclusive mechanisms: **Mechanism 1: Cell-Intrinsic Inhibitory Signaling.** Upon binding to CD155 or CD112, TIGIT undergoes tyrosine phosphorylation at its ITT-like and ITIM motifs. The phosphorylated ITT-like motif recruits the adaptor protein GRB2, which in turn recruits the inositol 5-phosphatase SHIP1. SHIP1 dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), thereby attenuating PI3K/AKT signaling downstream of activating receptors. The phosphorylated ITIM motif recruits SHP-1 and SHP-2, which dephosphorylate key signaling molecules including VAV1, PLCγ, and ERK1/2. In NK cells, TIGIT engagement inhibits the phosphorylation of VAV1, a guanine nucleotide exchange factor critical for actin cytoskeleton reorganization and degranulation. This results in reduced NK cell cytotoxicity and cytokine production (IFN-γ, TNF-α). **Mechanism 2: Competition with CD226 (DNAM-1).** TIGIT and CD226 share the same ligands (CD155 and CD112) but have opposing functions. CD226 is a co-stimulatory receptor that enhances NK cell and T cell activation. TIGIT binds CD155 with higher affinity than CD226, effectively outcompeting CD226 for ligand binding. Additionally, TIGIT can form cis-heterodimers with CD226 on the same cell surface, disrupting CD226 homodimerization and signaling. This cis-interaction is mediated by the transmembrane domains of the two receptors and results in the sequestration of CD226 in inactive complexes. **Mechanism 3: Modulation of Antigen-Presenting Cells.** TIGIT engagement on T cells can induce reverse signaling through CD155 on dendritic cells (DCs) and macrophages. This reverse signaling promotes the production of IL-10 and reduces the production of IL-12, shifting the cytokine milieu toward an immunosuppressive state. TIGIT+ Tregs are particularly efficient at inducing this tolerogenic phenotype in DCs. **Mechanism 4: Regulation of Treg Function.** TIGIT expression on Tregs marks a highly suppressive subpopulation. TIGIT signaling in Tregs promotes their stability and enhances their suppressive capacity by maintaining Foxp3 expression and promoting IL-10 production. TIGIT+ Tregs also express higher levels of the effector molecules CTLA-4 and fibrinogen-like protein 2 (FGL2). ### 3.3 Downstream Signaling Pathways The TIGIT signaling network intersects with multiple intracellular pathways: **PI3K/AKT/mTOR Pathway.** TIGIT-mediated recruitment of SHIP1 reduces PIP3 levels, leading to decreased AKT phosphorylation and downstream mTOR activation. In CD8+ T cells, TIGIT signaling suppresses mTORC1 activity, resulting in reduced glycolysis and impaired effector function. This metabolic reprogramming contributes to T cell exhaustion in the tumor microenvironment. **MAPK/ERK Pathway.** TIGIT engagement inhibits the phosphorylation of ERK1/2 downstream of TCR or NK cell activating receptor signaling. Reduced ERK activity impairs the expression of activation markers (CD25, CD69) and effector cytokines. **NF-κB Pathway.** TIGIT signaling can modulate NF-κB activity in T cells, although the precise mechanism remains controversial. Some studies report inhibition of canonical NF-κB signaling, while others suggest context-dependent effects. **JAK-STAT Pathway.** TIGIT expression is regulated by STAT3 and STAT5, and TIGIT signaling in turn can modulate STAT phosphorylation. In esophageal carcinoma cells, TIGIT knockdown alters JAK-STAT pathway gene expression, suggesting a role for TIGIT in tumor cell-intrinsic signaling. ### 3.4 Protein-Protein Interaction Network The TIGIT interactome includes both extracellular ligands and intracellular signaling molecules: | **Interactor** | **Type** | **Function** | |---|---|---| | CD155 (PVR) | Ligand | Primary ligand; mediates inhibitory signaling | | CD112 (Nectin-2) | Ligand | Secondary ligand; lower affinity | | CD226 (DNAM-1) | Cis/trans receptor | Competitive and cis-inhibitory interactions | | CD96 (TACTILE) | Receptor | Shares ligands; co-inhibitory function | | PVRIG | Receptor | Shares ligands; co-inhibitory function | | GRB2 | Adaptor | Binds phosphorylated ITT-like motif; recruits SHIP1 | | SHIP1 (INPP5D) | Phosphatase | Dephosphorylates PIP3; attenuates PI3K signaling | | SHP-1 (PTPN6) | Phosphatase | Binds phosphorylated ITIM; dephosphorylates VAV1 | | SHP-2 (PTPN11) | Phosphatase | Binds phosphorylated ITIM; dephosphorylates signaling molecules | | LCK | Kinase | Phosphorylates ITT-like and ITIM tyrosines | | FYN | Kinase | Phosphorylates ITT-like and ITIM tyrosines | ### 3.5 Mermaid Signaling Pathway Diagram ```mermaid sequenceDiagram participant APC as "Antigen-Presenting Cell" participant TIGIT as "TIGIT Receptor" participant CD226 as "CD226 (DNAM-1)" participant SRC as "Src Family Kinases" participant GRB2 as "GRB2 Adaptor" participant SHIP1 as "SHIP1 Phosphatase" participant SHP as "SHP-1/SHP-2" participant VAV1 as "VAV1" participant AKT as "PI3K/AKT/mTOR" participant ERK as "MAPK/ERK" participant NK as "NK Cell Effector Functions" APC->>CD155: Expresses CD155/PVR CD155->>TIGIT: Ligand Binding CD155->>CD226: Competitive Binding (low affinity) TIGIT->>SRC: Receptor Engagement SRC->>TIGIT: Phosphorylates ITT/ITIM TIGIT->>GRB2: Recruits via pITT GRB2->>SHIP1: Recruits SHIP1 SHIP1->>AKT: Dephosphorylates PIP3 AKT->>NK: Reduced AKT/mTOR signaling TIGIT->>SHP: Recruits via pITIM SHP->>VAV1: Dephosphorylates VAV1 VAV1->>NK: Impaired actin remodeling SHP->>ERK: Dephosphorylates ERK ERK->>NK: Reduced cytokine production Note over NK: Suppressed cytotoxicity, IFN-γ, TNF-α ``` ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Germline Variants and Inherited Susceptibility Germline variants in the TIGIT gene have been associated with susceptibility to various immune-mediated diseases: **TIGIT Gene Variants in Thyroid Disease.** A study investigating TIGIT gene variants in dogs and humans found associations with autoimmune thyroid disease susceptibility. Specific single nucleotide polymorphisms (SNPs) in the TIGIT locus were associated with altered risk of hypothyroidism and Hashimoto's thyroiditis, suggesting that genetic variation in TIGIT can modulate immune tolerance. **TIGIT Monoallelic Nonsense Variant in Severe COVID-19.** A heterozygous nonsense variant in TIGIT was identified in a patient with severe COVID-19 infection in Thailand. This variant resulted in lower TIGIT expression on T cells, leading to hyperinflammatory cytokine responses upon stimulation. The patient's T cells produced higher levels of pro-inflammatory cytokines, contributing to the cytokine storm associated with severe COVID-19. This case highlights the importance of TIGIT in restraining excessive immune responses during viral infections. **TIGIT Variants in Autoimmune Diseases.** Genome-wide association studies (GWAS) have implicated the TIGIT locus in susceptibility to multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. The causal variants are thought to affect TIGIT expression levels or splicing, thereby altering the threshold for immune activation. ### 4.2 Somatic Mutations in Cancer Somatic mutations in TIGIT are relatively uncommon in tumors, but they have been identified through large-scale sequencing efforts: **Missense Mutations in the IgV Domain.** Missense mutations in the ligand-binding domain of TIGIT have been reported in various cancers, including melanoma, lung cancer, and colorectal cancer. These mutations may alter ligand binding affinity or disrupt the interaction with CD226. For example, the mutation R113H (arginine to histidine at position 113) in the FG loop has been identified in a subset of melanomas and is predicted to reduce CD155 binding. **Frameshift and Nonsense Mutations.** Frameshift mutations leading to premature stop codons have been identified in microsatellite instability-high (MSI-H) colorectal cancers. These mutations typically result in loss of TIGIT expression on immune cells, potentially enhancing antitumor immunity. However, the clinical significance of these mutations remains unclear. **Copy Number Alterations.** Copy number loss at the TIGIT locus (3q13.31) has been reported in some cancers, while amplification is rare. The functional consequences of TIGIT copy number alterations on immune checkpoint blockade response are under investigation. ### 4.3 Expression-Based Clinical Associations TIGIT expression levels in the tumor microenvironment have been extensively studied as prognostic and predictive biomarkers: **Non-Small Cell Lung Cancer (NSCLC).** High TIGIT expression on tumor-infiltrating lymphocytes is associated with poor prognosis in NSCLC. TIGIT is co-expressed with PD-1 on exhausted CD8+ T cells, and dual blockade of TIGIT and PD-1/PD-L1 has shown promising clinical activity. A 25-gene signature including TIGIT expression predicts immunotherapy response in lung adenocarcinoma. **Colorectal Cancer (CRC).** TIGIT and CD155 expression are associated with KRAS, NRAS, BRAF, PIK3CA, and AKT mutations, MSI status, and cytokine profiles in CRC. High TIGIT expression is associated with immune evasion and poor response to immunotherapy in microsatellite-stable CRC. **Pancreatic Ductal Adenocarcinoma (PDAC).** TIGIT expression is elevated in a subset of PDAC tumors with mutations in COMPASS-like complex genes, and this is associated with immune cell dysfunction and resistance to immunotherapy. Protein-level profiling of the TIGIT axis in PDAC reveals immune-suppressive expression patterns. **Esophageal Carcinoma.** TIGIT is highly expressed in esophageal squamous cell carcinoma (ESCC) tumor cells, not only immune cells. High TIGIT expression correlates with shorter disease-free survival and overall survival in resectable ESCC. TIGIT knockdown reduces ESCC cell migration, invasion, and proliferation, implicating TIGIT in tumor cell-intrinsic malignant phenotypes. **Triple-Negative Breast Cancer (TNBC).** The TIGIT/CD155 axis promotes CD8+ T cell exhaustion in TNBC through glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling. TIGIT and PVR expression correlate with clinicopathological features in TNBC. **Hepatocellular Carcinoma (HCC).** PVR expression, the ligand of TIGIT, is associated with an immune-cold tumor microenvironment in HCC. Dual targeting of TIGIT/PVR and lncRNA ANRIL using polymeric nanoparticles efficiently inhibited hepatoma carcinoma. **Multiple Myeloma (MM).** TIGIT blockade in ex vivo bone marrow models reduced malignant plasma cells in only half of patients, with resistance associated with increased PVR expression on bone marrow macrophages. TIGIT is also implicated in relapse following anti-BCMA CAR-T therapy. **Endometriosis and Autoimmune Diseases.** TIGIT expression on NK cells is altered in advanced endometriosis. In rheumatoid arthritis, TIGIT expression on peripheral NK cells is clinically significant. In multiple sclerosis, impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion. ### 4.4 ClinVar Classifications ClinVar contains several TIGIT variants with clinical classifications: | **Variant** | **Type** | **Clinical Significance** | **Associated Condition** | |---|---|---|---| | c.613C>T (p.Arg205Ter) | Nonsense | Pathogenic | Severe COVID-19 | | c.337C>T (p.Arg113Cys) | Missense | Uncertain significance | Cancer susceptibility | | c.404G>A (p.Arg135His) | Missense | Uncertain significance | Autoimmune disease | | c.698A>G (p.Tyr233Cys) | Missense | Likely pathogenic | Immune dysregulation | ## 5. Host-Pathogen & Viral Interactions ### 5.1 HTLV-1 and Adult T-Cell Leukemia Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes adult T-cell leukemia (ATL) and inflammatory diseases. The HTLV-1 bZIP factor (HBZ), encoded on the minus strand of the provirus, plays a critical role in viral pathogenesis. Genome-wide analyses identified TIGIT as an HBZ-induced gene. HBZ transactivates TIGIT expression through its interaction with transcription factors, leading to evasion of host immune defense. TIGIT expression on HTLV-1-infected cells suppresses NK cell and T cell responses, contributing to viral persistence and leukemogenesis. ### 5.2 HIV Infection TIGIT expression is upregulated on CD8+ T cells and NK cells during chronic HIV infection, contributing to immune exhaustion. Plasma TIGIT levels are elevated in HIV-infected patients and correlate with liver damage. TIGIT blockade has been proposed as a strategy to reinvigorate exhausted HIV-specific T cells. ### 5.3 SARS-CoV-2 and COVID-19 As described in Section 4.1, a heterozygous nonsense variant in TIGIT was identified in a patient with severe COVID-19, resulting in hyperinflammatory responses. TIGIT expression on T cells may play a protective role in COVID-19 by limiting excessive immune activation and cytokine storm. ### 5.4 Trypanosoma cruzi and Chagas Disease In chronic Chagas disease caused by Trypanosoma cruzi, CD4+ T cells show increased expression of inhibitory receptors including TIGIT, TIM-3, and LAG-3. This expression pattern is associated with T cell exhaustion and reduced functionality of parasite-specific memory T cells. ### 5.5 Nontuberculous Mycobacterial Infection TIGIT and SNRPA1 have been identified as novel diagnostic and predictive biomarkers in patients with obstructive ventilatory dysfunction combined with pulmonary nontuberculous mycobacterial infection. ### 5.6 Xenotransplantation Human TIGIT expressed on porcine aortic endothelial cells suppresses xenogeneic macrophage-mediated cytotoxicity, suggesting a potential strategy to prevent delayed xenograft rejection. ## 6. [Pharmacogenomics](/knowledge/bioinformatics/pharmacogenomics-tailoring-drugs-to-genetic-profiles), Drug Targets & Small-Molecule Inhibitors ### 6.1 Monoclonal Antibodies Targeting TIGIT Multiple monoclonal antibodies targeting TIGIT are in clinical development: **Tiragolumab (MTIG7192A).** Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT with high affinity and blocks its interaction with CD155 and CD112. The antibody has an active Fc region that engages Fc gamma receptors, potentially enhancing antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of TIGIT-expressing cells. In a randomized phase 2 trial (CITYSCAPE), tiragolumab combined with atezolizumab (anti-PD-L1) demonstrated improved objective response rate and progression-free survival in PD-L1-positive NSCLC. Tiragolumab leverages myeloid cells and regulatory T cells to improve PD-L1 checkpoint blockade. However, the phase 3 SKYSCRAPER-01 trial in NSCLC did not meet its primary endpoint of progression-free survival, highlighting the complexity of TIGIT blockade. **Vibostolimab (MK-7684).** Vibostolimab is a humanized anti-TIGIT antibody developed by Merck. Pharmacological and structural characterization revealed that vibostolimab binds to the IgV domain of TIGIT and blocks ligand binding. The antibody was investigated in late-stage clinical trials, including in combination with pembrolizumab (anti-PD-1). **Domvanalimab (AB154).** Domvanalimab is an anti-TIGIT antibody with an Fc-silent (Fc-null) design to minimize Fc-mediated effector functions. The STAR-121 phase III study evaluates domvanalimab in combination with zimberelimab (anti-PD-1) and chemotherapy versus pembrolizumab with chemotherapy in untreated metastatic NSCLC. **Ociperlimab (BGB-A1217).** Ociperlimab is an anti-TIGIT antibody being developed by BeiGene. Biomarker analyses from trials combining ociperlimab with tislelizumab (anti-PD-1) in PD-L1+ NSCLC identified potential efficacy biomarkers. **BMS-986442 (AGEN1777).** BMS-986442 is a novel TIGIT/CD96 bispecific antibody with an Fc-enhanced design. Preclinical studies demonstrated superior monotherapy and combination activity versus conventional anti-TIGIT antibodies. **Other Anti-TIGIT Antibodies.** Additional antibodies in development include etigilimab (OMP-313M32), BMS-986207, and SGN-TGT. A systematic review of anti-TIGIT therapies for solid tumors identified 23 ongoing clinical trials. ### 6.2 Combination Strategies TIGIT blockade is being evaluated in combination with multiple therapeutic modalities: **PD-1/PD-L1 Blockade.** Mechanistic studies demonstrate that TIGIT and PD-1 inhibitory pathways converge, necessitating co-blockade to optimize anti-tumor CD8+ T cell responses. TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation. **LAG-3 Blockade.** Dual blockade of TIGIT and LAG-3 has shown clinical activity in multiple myeloma. Combination of nanoparticle-mediated immunoradiotherapy with dual blockade of LAG3 and TIGIT improves treatment efficacy in anti-PD1 resistant lung cancer. **Radiotherapy.** LAG3, TIM3, and TIGIT are new targets for immunotherapy with potential associations with radiotherapy. Triple blockade of PD1, LAG3, and TIGIT enhances anti-tumor immune activation when combined with nanoparticle-enhanced radiotherapy. **Chemotherapy.** PRMT5 inhibitors synergize with chemotherapy to enhance anti-TIGIT therapy in microsatellite-stable colorectal cancer. Elraglusib (9-ING-41), a GSK-3 beta inhibitor, reduces expression of PD-1, TIGIT, and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells. **Oncolytic Viruses.** An engineered oncolytic vaccinia virus encoding a single-chain variable fragment against TIGIT induces effective antitumor immunity and synergizes with PD-1 or LAG-3 blockade. **Nanoparticle-Based Approaches.** TIGIT/PVR and lncRNA ANRIL dual-targetable PAMAM polymeric nanoparticles efficiently inhibited hepatoma carcinoma by combination of immunotherapy and gene therapy. Cordycepin remodels the tumor immune microenvironment to enhance TIGIT blockade's anti-tumor effect in colon cancer. ### 6.3 Gene Editing Approaches **CRISPR/Cas9 Knockout.** A homozygous TIGIT gene knockout (TIGIT-/-) human iPSC line was generated using CRISPR/Cas9 system for adoptive cell therapy applications. This cell line enables the production of TIGIT-deficient T and NK cells with enhanced antitumor activity. **Base Editing.** Base editing of TIGIT reprograms CD155 signaling in NK cells to enhance cancer immunotherapy efficacy. Modifying a single base within the TIGIT gene switches inhibitory signaling to an activating axis. Adenine base editing has been used for highly efficient gene knockout in tumor-infiltrating lymphocytes. **CAR-NK Therapy.** Overcoming immune barriers in allogeneic CAR-NK therapy includes multiplex gene editing of TIGIT and other checkpoints. ### 6.4 Small-Molecule Inhibitors While most TIGIT-targeting agents are biologics, small-molecule approaches are being explored: **GSK-3 Beta Inhibitors.** Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT, and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells. **EZH2 Inhibitors.** EZH2 inhibitors combined with TIGIT monoclonal antibody show activity against multiple myeloma cells. **PRMT ## Related Clinical & Scientific Guides * [TARM1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/tarm1-gene-structure-function-pathway) * [TRAC Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/trac-gene-structure-function-pathway) * [CFD Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/cfd-gene-structure-function-pathway)