TIGIT

Overview

TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains) is an inhibitory immune checkpoint receptor expressed predominantly on T cells, natural killer (NK) cells, and regulatory T cell subsets. Structurally, TIGIT contains an extracellular immunoglobulin variable domain, a transmembrane region, and an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM), through which it transduces suppressive signals upon engagement with its principal ligand CD155 (PVR). By dampening T cell and NK cell activation downstream of CD155 signaling, TIGIT functions as a critical brake on immune responses, contributing to peripheral tolerance and the prevention of autoimmunity. Alongside canonical checkpoints such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4), the programmed cell death 1, LAG3, and TIM-3, TIGIT has been classified as a key regulator of immune homeostasis whose dysregulation in pathological contexts—most notably cancer—enables immune evasion by malignant cells.

TIGIT has emerged as a prominent target in immuno-oncology, attracting substantial interest as a complement or alternative to established PD-1/PD-L1 blockade. Its immunosuppressive pathways are distinct but interconnected with those engaged by PD-1, providing a rationale for combinatorial therapeutic strategies. Beyond oncology, accumulating evidence implicates TIGIT in autoimmune and inflammatory disease contexts, as well as in the regulation of vaccine-induced adaptive immunity, broadening its relevance across the spectrum of translational immunology.

Focus of Latest Publications

Immune Checkpoint Biology and Cancer Immunotherapy

TIGIT has consolidated its position as a notable immune checkpoint in tumor immunotherapy, widely regarded as the most clinically advanced target following PD-1/PD-L1. A 2026 landscape analysis of TIGIT-targeted cancer clinical trials (PMID: 42142605) documented the global trajectory of this field, noting that while TIGIT rapidly advanced through early-phase development, recent Phase III trial setbacks have tempered the early optimism that surrounded the target. This analysis highlighted geographic shifts in trial activity and drew attention to policy implications for how checkpoint inhibitors beyond the PD-1/PD-L1 axis are prioritized and resourced globally.

A central rationale for TIGIT-directed therapy rests on its mechanistic complementarity with PD-1. As demonstrated in the randomized phase 2 ARC-10 study (PMID: 41830668), domvanalimab (an anti-TIGIT antibody) was combined with zimberelimab (an anti-PD-1 therapy antibody) as first-line treatment in patients with PD-L1-high, advanced non-small cell lung cancer (stage IIIB–IV). The study's scientific premise was that TIGIT and PD-1 trigger distinct but interconnected immunosuppressive pathways, making dual blockade mechanistically synergistic. Results from Part 1 of ARC-10 supported the feasibility and preliminary efficacy of this combination in a PD-L1-high enriched population.

In parallel, TIGIT has been characterized as a non-classical immune checkpoint operating through metabolic and signaling mechanisms distinct from the canonical PD-1/PD-L1 axis. A review of emerging checkpoints in breast cancer (PMID: 42059928) grouped TIGIT alongside IDO1, IL4I1, and VISTA as targets mediating immune escape through non-redundant pathways, underscoring the complexity of the tumor microenvironment and the need for multi-target immunotherapeutic approaches.

TIGIT in Lymphoid Malignancies

In classical Hodgkin lymphoma, a dedicated clinicopathological study (PMID: 42049433) characterized the expression patterns of TIGIT, identifying it as an immune checkpoint receptor involved in the immune evasion of tumor cells and positioning it as a putative target for novel immunotherapies in this lymphoid malignancy context. Separately, analysis of the T-cell acute lymphoblastic leukemia (T-ALL) tumor microenvironment in patients enrolled in the AALL0434 clinical trial (PMID: 41671457) identified a subpopulation of bone marrow-enriched CCR4+ FOXP3+ T-regulatory cells co-expressing PD-1 and TIGIT. This regulatory T cell subset was identified as potentially targetable through anti-CCR4 therapy, illustrating how TIGIT co-expression marks immunosuppressive populations within leukemic bone marrow niches.

TIGIT in NK Cell Biology and Engineered Immunotherapies

The role of TIGIT in NK cell biology has received increasing attention. A 2026 study employing base-editing technology to modify primary human NK cells (PMID: 41982126) achieved greater than 90% editing efficiency of the TIGIT gene in peripheral blood-derived NK cells, generating TIGIT base-edited NK (TIGIT BE-NK) cells. This approach reprogrammed CD155 signaling in NK cells, demonstrating enhanced cancer immunotherapy efficacy and establishing precision gene editing as a viable strategy to overcome TIGIT-mediated NK cell suppression.

In a complementary line of investigation, bacteria-trained NK (stNK) cells generated using Salmonella enterica were evaluated in orthotopic metastatic models (PMID: 42237539). These engineered NK cells significantly outperformed conventional immune checkpoint therapies—including both PD-1 and TIGIT blockade—in preventing cancer metastasis, highlighting that the unique immunological mechanisms engaged by bacteria-trained NK cells operate through pathways beyond those addressed by checkpoint blockade alone. This finding raises important questions about the ceiling of benefit achievable through TIGIT inhibition in the metastatic setting.

TIGIT in Solid Tumor Microenvironment Remodeling

In renal cancer, a supramolecular therapeutic strategy integrating TIGIT blockade with vascular normalization was described (PMID: 41705472). The molecule RING1 incorporated both VEGF/Tie2-targeting and TIGIT-blocking modules within a single construct, enabling spatiotemporally synchronized vascular normalization, CD8+ T cell infiltration, and checkpoint inhibitor. This multi-functional design reflects broader efforts to co-target the immunosuppressive tumor microenvironment at multiple nodes simultaneously.

TIGIT in Autoimmune and Inflammatory Disease

Beyond oncology, a study in rheumatoid arthritis and spondyloarthritis (PMID: 42161414) characterized PD-1+ TIGIT+ CD4+ effector memory T cells as a clinically predictive biomarker subset. Co-expression of PD-1 and TIGIT on CD4+ T cells at baseline was associated with response to anti-TNF therapy, suggesting that this immune checkpoint signature reflects a particular state of T cell activation or exhaustion that is responsive to biologic intervention. This finding positions TIGIT co-expression as a tool for stratifying patients in autoimmune conditions.

TIGIT in Vaccine Immunology

TIGIT's role extends to adaptive immune responses induced by vaccination. In a study examining pre-vaccination immune signatures in children with inborn errors of immunity in the context of COVID-19 vaccines (PMID: 42027105), activated memory B cells and peripheral T follicular helper cells from high vaccine responders exhibited greater induction of activation and memory-related genes, including NFKB1, CD69, TIGIT, CD40L, and BATF. This upregulation in the high-responder group was interpreted as reflecting greater intrinsic cellular readiness to support coordinated antibody production, situating TIGIT expression within the transcriptional programs that underpin effective humoral vaccine responses.

Key Publications

• Jun Therapeutic bacteria-trained NK cells confer long-term protection against cancer metastasis. (Molecular therapy : the journal of the American Society of Gene Therapy, 2026, PMID 42237539): "stNK cells significantly outperform conventional immune checkpoint therapies, including PD-1 and TIGIT blockade, in preventing metastasis, underscoring the unique immunological mechanisms in combating metastasis."
• Jun The global landscape of TIGIT-targeted cancer clinical trials: Trends, geographic shift, and policy implications. (Journal of cancer policy, 2026, PMID 42142605): "TIGIT has emerged as a notable immune checkpoint in tumor immunotherapy following PD-1/L1, though recent Phase III setbacks have tempered early optimism."
• May PD1+ TIGIT+ CD4+ T cells predict response to anti-TNF in rheumatoid arthritis and spondyloarthritis. (RMD open, 2026, PMID 42161414): "Programmed cell death protein 1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are immune checkpoints expressed on T cells."
• May Expression Patterns of T-cell immunoreceptor With Ig and ITIM domains (TIGIT) in Classical Hodgkin Lymphoma: A Clinicopathological Study. (In vivo (Athens, Greece), 2026, PMID 42049433): "T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) is an immune checkpoint receptor involved in the immune evasion of malignant cells and a putative target for novel immunotherapies."
• May Domvanalimab combined with zimberelimab as first-line treatment in patients with PD-L1-high, advanced non-small cell lung cancer: Results from the randomized phase 2 ARC-10 study, Part1. (Lung cancer (Amsterdam, Netherlands), 2026, PMID 41830668): "TIGIT and PD-1 trigger distinct but interconnected immunosuppressive pathways."
• May Metabolic enzymes and immune receptors as emerging checkpoints in breast cancer: mechanisms, clinical trials, and therapeutic implications. (Naunyn-Schmiedeberg's archives of pharmacology, 2026, PMID 42059928): "...non-classical immune checkpoints such as IDO1, IL4I1, VISTA, and TIGIT, which mediate immune escape through metabolic and signaling pathways distinct from the PD-1/PD-L1 axis."
• Apr Supramolecular net-suppressor drives tumor vascular-immune microenvironment remodeling with spatiotemporal synchronization for renal cancer therapy. (Materials horizons, 2026, PMID 41705472): "RING1 incorporates VEGF/Tie2-targeting and TIGIT-blocking modules within one molecule, enabling the simultaneous induction of vascular normalization, effector T cell infiltration, and immune checkpoint blockade."
• Apr CCR4 expression defines a targetable subset of T-cell acute lymphoblastic leukemia. (Blood advances, 2026, PMID 41671457): "We analyzed the T-ALL microenvironment from 40 patients treated on the AALL0434 clinical trial and identified a subpopulation of bone marrow-enriched CCR4+ FOXP3+ T-regulatory cells that express immune checkpoints (PD-1 and TIGIT) and could be targeted with anti-CCR4 therapy."
• Apr Pre-vaccination immune signatures of children with inborn errors of immunity associate with COVID-19 vaccine response. (Human vaccines & immunotherapeutics, 2026, PMID 42027105): "Activated memory B cells and peripheral T follicular helper cells from high responders exhibited greater induction of activation and memory-related genes, including NFKB1, CD69, TIGIT, CD40L, and BATF, indicating greater intrinsic readiness to support coordinated antibody production."
• Apr Base Editing of TIGIT Reprograms CD155 Signaling in Natural Killer Cells to Enhance Cancer Immunotherapy Efficacy. (Cancer research, 2026, PMID 41982126): "In this study, we applied base-editing technology to precisely modify signal transduction in primary human NK cells, which achieved a high editing efficiency of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) gene (>90%) in peripheral blood-derived NK (TIGIT BE-NK) cells."