TIGIT is an immune checkpoint receptor found on the surface of T cells and natural killer cells, and it has become one of the most closely watched targets in cancer immunotherapy over the past several years. The basic idea is familiar from existing checkpoint drugs: tumors exploit TIGIT to shut down the immune cells that would otherwise attack them, and blocking TIGIT with an antibody could release that brake. What makes TIGIT particularly interesting is that it operates through a different pathway than PD-1, the checkpoint behind blockbuster drugs like pembrolizumab and nivolumab, raising the possibility that combining both approaches could help patients who don’t respond to PD-1 blockade alone. The clinical story so far, though, has been far messier than the preclinical promise suggested.
How TIGIT Suppresses the Immune Response
TIGIT belongs to a family of receptors that all compete for the same set of partners on the surfaces of tumor cells and antigen-presenting cells. The most important of those partners is a protein called CD155, which is overexpressed on many cancers. When TIGIT grabs CD155, it sends an inhibitory signal into the T cell or NK cell, essentially telling it to stand down. But CD155 is also a target for CD226, a different receptor that sends the opposite signal, an activating one. TIGIT outcompetes CD226 for access to CD155, which means it can suppress immune activation in two ways at once: it delivers its own “stop” signal while also preventing CD226 from delivering a “go” signal.
This competition has been considered the central mechanism by which TIGIT dampens anti-tumor immunity. The receptor also binds other ligands like CD112 and CD113, but with much lower affinity, making the TIGIT-CD155 interaction the one that matters most clinically.
1Journal for ImmunoTherapy of Cancer. TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy TIGIT also signals through internal motifs in its tail that recruit proteins to actively dampen T cell activation once the receptor is engaged.2bioRxiv. Inhibitory TIGIT signalling is dependent on T cell receptor activation
The result is a receptor that acts as a multi-layered brake. It blocks the activating receptor, it signals suppression directly, and it promotes an immunosuppressive environment by encouraging regulatory T cells and tolerogenic immune signaling. Tumors that overexpress CD155 can exploit this entire system to shield themselves from immune attack.
Why TIGIT and PD-1 Make a Natural Pair
The most compelling reason TIGIT attracted so much attention from drug developers is its relationship with PD-1. In tumor samples, TIGIT tends to show up on the same exhausted T cells that express high levels of PD-1. In bladder cancer, for instance, TIGIT was the most frequently co-expressed checkpoint receptor on PD-1-positive tumor-infiltrating T cells, and blocking TIGIT enhanced the effect of PD-1 blockade on those cells’ ability to produce immune-signaling molecules.3PubMed. TOX-expressing terminally exhausted tumor-infiltrating CD8(+) T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer Preclinical work across several cancer types showed that co-blocking TIGIT and PD-1 could enhance tumor rejection more than either blockade alone.4PubMed Central. Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials
This made intuitive sense. If a tumor is using multiple brakes simultaneously, releasing just one might not be enough. PD-1 blockade has transformed outcomes in melanoma, lung cancer, and other tumor types, but a large fraction of patients still don’t respond. The hope was that adding TIGIT blockade could convert some of those non-responders into responders by removing a second layer of immune suppression.
Biomarker data supported this logic. In lung squamous cell carcinoma, high TIGIT density on tumor-infiltrating immune cells correlated with PD-1 and PD-L1 expression, suggesting the two pathways are co-activated in the same tumors.5PubMed Central. PVR/TIGIT and PD-L1/PD-1 expression predicts survival and enlightens combined immunotherapy in lung squamous cell carcinoma Separately, researchers found that CD155 expression levels influenced how well patients responded to PD-1 blockade: among patients whose tumors expressed PD-L1, those with high CD155 were enriched for non-responders to anti-PD-1 therapy, while those with low CD155 were enriched for responders.6PubMed Central. Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade This suggested that the TIGIT-CD155 axis might be a key reason PD-1 blockade fails in some patients, making it a logical second target.
The Fc Engineering Question
One design decision that distinguishes anti-TIGIT antibodies from anti-PD-1 drugs is whether the antibody’s “tail” (the Fc region) should be active or inert. PD-1-blocking antibodies are typically engineered so their Fc region does not trigger immune cell killing, because you don’t want to destroy the very T cells you’re trying to activate. TIGIT creates a different situation. TIGIT is expressed at especially high levels on regulatory T cells (Tregs), the immunosuppressive cells that tumors recruit to protect themselves. An anti-TIGIT antibody with an active Fc region could do double duty: block TIGIT’s inhibitory signal on effector T cells while simultaneously tagging Tregs for destruction by natural killer cells.
Preclinical data bore this out. In mice and human blood samples, the high TIGIT expression on Tregs made them particularly vulnerable to antibody-dependent killing, and anti-TIGIT antibodies engineered with Fc-active formats showed stronger anti-tumor activity than their Fc-silent counterparts.7PubMed. Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies In one study, the reduction of intratumoral Tregs by an Fc-active anti-TIGIT antibody appeared to unleash additional T cell responses against tumor proteins that had previously been kept in check, and engineering the Fc region for even stronger effector functions further improved anti-tumor efficacy.8The Journal of Immunology. A Cross-Species Reactive TIGIT-Blocking Antibody Fc Dependently Confers Potent Antitumor Effects
This distinction is not academic. Different pharmaceutical companies have made different bets. Roche’s tiragolumab uses an Fc-active format. Others, like domvanalimab, use Fc-silent designs. If Treg depletion turns out to be essential for clinical benefit, Fc-silent antibodies may underperform regardless of how well they block TIGIT signaling. If Treg depletion drives too much autoimmunity, the Fc-active approach could backfire. The field hasn’t resolved this question yet, and the divergent clinical results may partly reflect these design choices.
A Promising Start and a Complicated Follow-Up in Lung Cancer
The clinical development of tiragolumab in non-small-cell lung cancer (NSCLC) illustrates how a target can look transformative in early trials and then prove difficult to confirm at scale. The phase 2 CITYSCAPE trial tested tiragolumab plus the PD-L1 inhibitor atezolizumab against atezolizumab alone as first-line treatment in patients with PD-L1-positive NSCLC. The results were encouraging: about 31% of patients in the combination arm had an objective tumor response compared to about 16% with atezolizumab alone, and median progression-free survival was 5.4 months versus 3.6 months.9The Lancet Oncology. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as first-line treatment in patients with PD-L1-selected non-small-cell lung cancer (CITYSCAPE)
These results fueled enormous excitement and a large phase 3 program. But the confirmatory trials have told a more sobering story. SKYSCRAPER-01, a large phase 3 trial in patients with high PD-L1 expression, did not meet its primary endpoint. Median progression-free survival was 7.0 months with the combination versus 5.6 months with placebo plus atezolizumab, but this difference did not reach the pre-specified significance threshold. Overall survival showed a numerical trend favoring the combination (23.1 versus 16.9 months) but was also not statistically significant.10PubMed Central. SKYSCRAPER-01: Tiragolumab in Combination With Atezolizumab in Previously Untreated PD-L1-High, Locally Advanced, Unresectable or Metastatic Non-Small Cell Lung Cancer
SKYSCRAPER-06, which tested tiragolumab plus atezolizumab plus chemotherapy against the current standard of pembrolizumab plus chemotherapy, fared worse. The combination arm showed shorter progression-free survival (8.3 versus 9.9 months) and shorter overall survival (18.9 versus 23.1 months) compared to the standard-of-care arm.11JAMA Oncology. Tiragolumab Plus Atezolizumab and Chemotherapy for Advanced Nonsquamous Non–Small Cell Lung Cancer: The Phase 3 SKYSCRAPER-06 Randomized Clinical Trial And in small-cell lung cancer, the phase 3 SKYSCRAPER-02 trial found no benefit when tiragolumab was added to atezolizumab and chemotherapy.12PubMed Central. Tiragolumab (Anti-TIGIT) in SCLC: Skyscraper-02, a Towering Inferno
The gap between CITYSCAPE’s promising signal and the SKYSCRAPER program’s disappointing readouts is one of the defining puzzles of the anti-TIGIT field. Phase 2 trials are smaller, and effect sizes often shrink in larger confirmatory studies. But the SKYSCRAPER-06 result, where the experimental arm actually performed worse than standard-of-care, raised questions about whether the atezolizumab backbone (rather than pembrolizumab) might have contributed to the failure, or whether the combination simply doesn’t add meaningful benefit in an unselected population.
Safety Profile
One piece of relatively encouraging news from the clinical program is that anti-TIGIT antibodies have generally been tolerable. In the first-in-human trial of vibostolimab (Merck’s anti-TIGIT antibody), no dose-limiting toxicities were reported. Among patients receiving vibostolimab alone, about 56% experienced treatment-related side effects, mostly fatigue and itching. Combining it with pembrolizumab pushed that rate to 62%, with itching and rash being the most common complaints. Serious (grade 3-4) side effects occurred in 9% of patients on monotherapy and 17% on the combination.13PubMed. First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer
A systematic review and meta-analysis of tiragolumab plus atezolizumab across five randomized trials involving about a thousand patients found that the combination was associated with significantly higher rates of rash, itching, and infusion-related reactions compared to atezolizumab alone, but there were no significant increases in gastrointestinal, blood-related, or endocrine side effects, and the rate of high-grade adverse events was not significantly different between groups.14PubMed. Safety profile of dual TIGIT and PD-L1 blockade with tiragolumab plus atezolizumab in solid tumors: a systematic review and meta-analysis of randomized controlled trials Skin-related reactions (rash, itching) appear to be the signature side effect of TIGIT blockade, which is consistent with the receptor’s role in immune regulation at barrier surfaces.
Structural Surprises About TIGIT Binding
A common narrative in the field has been that TIGIT “outcompetes” CD226 for CD155 because TIGIT binds CD155 with far higher affinity, often described as nanomolar-range binding versus the weaker interaction between CD226 and CD155.15Journal for ImmunoTherapy of Cancer. TIGIT in cancer immunotherapy But newer biophysical work has challenged this assumption. Detailed binding measurements suggest that all the receptors in this family, including TIGIT, interact with CD155 at relatively weak (micromolar-range) affinities, and that TIGIT’s dominance over CD226 may come less from inherently tighter binding and more from TIGIT simply being expressed at higher levels on the cell surface.16PubMed Central. Biophysical characterization of PVR family interactions and therapeutic antibody recognition to TIGIT
This distinction matters for drug development. If TIGIT wins the competition primarily through abundance rather than affinity, then blocking TIGIT with an antibody might not fully restore CD226-mediated activation because other inhibitory receptors in the same family (like CD96 and CD112R) could still be present at high levels. Crystal structures of anti-TIGIT antibodies like tiragolumab and ociperlimab in complex with TIGIT show that these drugs physically clash with CD155’s binding site, confirming they prevent the TIGIT-CD155 interaction.17PubMed. Structural insights into the unique pH-responsive characteristics of the anti-TIGIT therapeutic antibody Ociperlimab But if the real immunosuppressive effect comes from the sheer density of inhibitory receptors rather than any single one, monotherapy against TIGIT alone may have limited impact, which aligns with the generally underwhelming monotherapy results seen clinically.
Next-Generation Approaches
Given the mixed results with straightforward anti-TIGIT antibodies, researchers are exploring more creative designs. One promising direction involves bispecific antibodies, molecules engineered to grab two targets at once. A bispecific antibody targeting both CD25 (a marker of regulatory T cells) and TIGIT was shown to selectively deplete the double-positive cells (those expressing both CD25 and TIGIT) that are among the most suppressive cells in the tumor environment. In mouse models, this bispecific outperformed either single-target antibody alone and achieved anti-tumor activity without depleting the regulatory T cells circulating elsewhere in the body, which is important for avoiding autoimmune side effects.18PubMed Central. A CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion
There is also interest in combining TIGIT blockade with CAR-T cell therapy, though early results here have been humbling. In a multiple myeloma mouse model, adding a TIGIT-blocking antibody to CAR-T cells improved killing in the lab dish but did not improve survival in mice. A “fourth-generation” CAR-T cell engineered to secrete its own TIGIT blocker also failed to improve outcomes. Knocking TIGIT out of the CAR-T cells entirely using CRISPR gene editing showed a trend toward better survival, but the improvement did not clearly outperform standard CAR-T cells.19PubMed. TIGIT blockade in the context of BCMA-CART cell therapy does not augment efficacy in a multiple myeloma mouse model These findings suggest that TIGIT’s importance may vary significantly by cancer type, immune context, and therapeutic modality.
TIGIT as a Biomarker Independent of Therapy
Separate from its role as a drug target, TIGIT expression in tumors may carry prognostic information. In small-cell lung cancer, patients whose tumors showed high TIGIT expression had significantly longer disease-free survival and overall survival, and they responded better to both chemotherapy and immunotherapy.20PubMed Central. Exploring the role of TIGIT in patients with Small Cell Lung Cancer as a novel predictor of prognosis and immunotherapy response This is paradoxical at first glance: if TIGIT suppresses anti-tumor immunity, why would high TIGIT expression predict better outcomes? The likely explanation is that high TIGIT expression is a proxy for having a lot of immune cells in the tumor in the first place. Tumors heavily infiltrated by T cells tend to do better regardless, and those T cells naturally express TIGIT as part of their exhaustion program. The TIGIT isn’t helping; it’s just a marker of the immune response that is.
In classic Hodgkin lymphoma, researchers have developed scoring systems for TIGIT expression on the immune cells surrounding the cancerous Reed-Sternberg cells, grading tumors from score 0 (no TIGIT-positive immune cells) to score 3 (intense rings of TIGIT-positive cells around the tumor cells).21Scientific Reports. A novel scoring system for TIGIT expression in classic Hodgkin lymphoma Whether these scores predict response to specific therapies is still being studied, but the work illustrates how TIGIT expression patterns might eventually help guide treatment decisions.
TIGIT’s Role in Autoimmune Disease
The flip side of releasing immune brakes to fight cancer is the risk of unleashing autoimmunity, and TIGIT’s biology illustrates this tension well. In animal models, blocking the TIGIT pathway or deleting TIGIT genetically led to overactivation and proliferation of T cells, worsened inflammation, and increased susceptibility to autoimmune conditions.15Journal for ImmunoTherapy of Cancer. TIGIT in cancer immunotherapy TIGIT suppresses the T helper cells that drive autoimmune pathology through at least three distinct routes: directly inhibiting T cell activation, inducing tolerogenic antigen-presenting cells that produce the anti-inflammatory molecule IL-10, and promoting regulatory T cell function through additional suppressive factors.22Cell Press. Co-inhibitory Receptors in the Context of Immune Diseases
This has practical implications in both directions. For cancer immunotherapy, it means that anti-TIGIT drugs carry an inherent risk of immune-related adverse events, particularly in tissues where TIGIT normally keeps inflammation in check. The skin-related side effects already observed in trials fit this pattern. For autoimmune disease, TIGIT agonists (drugs that activate the receptor rather than blocking it) are being explored as a way to dial down pathological immune responses in conditions like multiple sclerosis and inflammatory bowel disease. The same molecule that oncologists want to block, rheumatologists might want to stimulate. That duality makes TIGIT one of the more biologically interesting checkpoint targets, even if the cancer therapy story remains a work in progress.