T-cell Immunoreceptor with Ig and ITIM domains, known as TIGIT, is a protein found on the surface of several types of immune cells, including T-cells and natural killer (NK) cells. It functions as an inhibitory receptor, meaning it is part of the body’s natural “immune checkpoint” system, which regulates the intensity and duration of an immune response. The primary role of TIGIT is to apply a brake on immune cell activity, preventing over-activation that could damage healthy tissues. Understanding this biological mechanism is now paramount in medicine, as researchers are exploring how to manipulate this system to create new treatments.
How TIGIT Regulates the Immune System
TIGIT acts as an “off switch” to maintain balance within the immune system, ensuring immune responses are controlled and temporary. This regulatory function is achieved when TIGIT binds to its ligands, such as Poliovirus Receptor (PVR), also known as CD155, found on surrounding cells. Once binding occurs, TIGIT sends an inhibitory signal into the immune cell via its intracellular domain, which contains an ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif).
This inhibitory signal dampens the T-cell’s ability to proliferate and produce effector cytokines, which are signaling molecules necessary for coordinating an attack. TIGIT also exerts its suppressive effect by competing with a co-stimulatory receptor called CD226 (DNAM-1), which acts as an “accelerator” for the T-cell. TIGIT binds to the PVR ligand with a higher affinity than CD226, effectively blocking the stimulatory signal and ensuring the immune cell remains suppressed.
The presence of TIGIT on immune cells safeguards against autoimmunity, where the immune system mistakenly attacks healthy cells. For example, after an infection is cleared, TIGIT helps turn down the inflammatory response, bringing the system back to a resting state. TIGIT is also highly expressed on Regulatory T-cells (Tregs), where its engagement enhances their suppressive function against other immune cells.
TIGIT’s Role in Cancer and Immune Evasion
Cancer cells exploit the TIGIT pathway to shield themselves from destruction by infiltrating immune cells, a process known as immune evasion. Tumors frequently overexpress TIGIT’s ligands, particularly PVR/CD155, on their own surfaces and on supporting cells within the tumor microenvironment (TME). This overexpression creates a constant inhibitory signal, continuously engaging the TIGIT receptors on the T-cells and NK cells that have entered the tumor area.
The persistent inhibitory signaling drives the T-cells into a state of dysfunction, often described as T-cell exhaustion, which leaves them unable to mount an effective anti-tumor response. TIGIT contributes to the overall immunosuppressive nature of the TME by enhancing the activity of Regulatory T-cells. These Tregs, which highly express TIGIT, actively suppress the cytotoxic T-cells that are attempting to kill the cancer.
This collective action—direct inhibition of killer cells, blocking of co-stimulatory signals, and enhancement of Treg suppression—paralyzes the immune attack. This mechanism allows the tumor to grow and spread unchecked. Researchers have identified TIGIT as a target for immunotherapy aimed at re-awakening the exhausted immune cells.
Developing Therapies to Block TIGIT
The therapeutic strategy behind targeting TIGIT is to remove the “brakes” that the cancer has applied to the immune system. TIGIT inhibitor drugs are primarily monoclonal antibodies (mAbs), engineered proteins designed to bind specifically to the TIGIT receptor on immune cells. By binding to TIGIT, these antibodies block the receptor from interacting with its ligands, like PVR/CD155, on the tumor cells.
This blockade prevents the inhibitory signal from being transmitted into the T-cell, restoring the immune cell’s function and its ability to attack cancer. The resulting re-activation leads to increased proliferation and the production of pro-inflammatory cytokines necessary for tumor destruction. TIGIT blockade also enhances the cytotoxic capability of Natural Killer cells and reduces the suppressive power of Regulatory T-cells, offering a broader mechanism of immune activation.
Examples of these anti-TIGIT antibodies include agents like vibostolimab, tiragolumab, and belrestotug, which are all being investigated in various stages of clinical development. The goal is to use these agents to unleash the body’s own immune system to recognize and eliminate cancerous cells. While preclinical data has shown strong potential, the effectiveness of TIGIT inhibition in a clinical setting is largely being studied in combination with other immunotherapies.
Clinical Trials and Combination Treatment Strategies
TIGIT inhibitors are rarely used as a monotherapy in clinical practice because they are intended to work synergistically with other treatments. The most common approach involves combining an anti-TIGIT antibody with a PD-1 or PD-L1 inhibitor, creating a dual checkpoint blockade. The logic is that PD-1/PD-L1 inhibitors remove one layer of immune suppression, while TIGIT inhibitors remove a distinct, non-redundant second layer, leading to a more potent and comprehensive anti-tumor response.
This combination strategy has shown encouraging results in various solid tumors, focusing on Non-Small Cell Lung Cancer (NSCLC) and melanoma. For instance, a Phase 2 trial (GALAXIES Lung-201) investigating belrestotug alongside the anti-PD-1 drug dostarlimab in NSCLC patients demonstrated a confirmed overall response rate of approximately 60% in some dosing groups, compared to 28.1% with PD-1 monotherapy. Targeting both pathways simultaneously can significantly improve patient outcomes.
While earlier Phase 3 trials involving the anti-TIGIT agent tiragolumab faced some setbacks, the overall clinical pipeline remains robust, with numerous candidates like ociperlimab and vibostolimab continuing to advance. The ongoing research focuses on identifying which cancers and patient subsets will benefit most from this dual blockade, as well as exploring combinations with chemotherapy and other novel agents. This combination approach represents a major step in overcoming resistance to existing immunotherapies and expanding treatment options for patients.