Immunotherapy represents a transformative shift in cancer treatment, moving beyond traditional methods that directly target tumor cells. This approach focuses on marshaling the patient’s own biological defenses to attack malignant growth. By activating and strengthening natural defensive cells, immunotherapy aims for a sustained and specific anti-cancer response. This strategy enables the immune system to destroy cancer cells and develop long-lasting immunological memory, offering durable disease control and improved outcomes for individuals with advanced cancers.
The Role of TIGIT in Immune Regulation
The immune system uses a network of “checkpoint” molecules to prevent defensive cells from attacking healthy tissues. T-cell Immunoreceptor with Immunoglobulin and ITIM domains (TIGIT) is one such inhibitory receptor, acting like a brake on the immune response. TIGIT is highly expressed on activated T-cells, Natural Killer (NK) cells, and immunosuppressive regulatory T-cells.
When TIGIT is engaged, it dampens the immune cell’s activity, reducing its ability to proliferate and release cancer-fighting chemicals. Tumors exploit this pathway by overexpressing ligands, such as CD155 (PVR) and CD112, that bind to TIGIT. The high concentration of these ligands in the tumor microenvironment subjects infiltrating immune cells to TIGIT-mediated inhibitory signals. This suppression leads to T-cell exhaustion, a major mechanism by which cancer evades immune elimination.
The TIGIT pathway also enhances the immunosuppressive function of regulatory T-cells, further contributing to the hostile environment surrounding the tumor. Blocking TIGIT offers a way to disarm the tumor’s primary defense mechanism against the body’s immunological attack.
How Anti-TIGIT Drugs Boost Immune Response
Anti-TIGIT drugs are monoclonal antibodies engineered to block the TIGIT receptor on T-cells and NK cells. By binding to TIGIT, these antibodies prevent the receptor from engaging its ligands on tumor or immune cells. This action releases the immunological “brake,” allowing defensive cells to reactivate and destroy cancer cells. Removing this inhibitory signal promotes the proliferation and cytotoxic function of effector T-cells, resulting in a robust anti-tumor response.
TIGIT’s biology involves direct competition with the activating receptor CD226, which shares ligands like CD155. TIGIT has a higher affinity for these ligands than CD226, effectively monopolizing the binding sites and shutting down the activating signal. Anti-TIGIT antibodies restore balance by blocking TIGIT, allowing the CD226 pathway to become fully operational and transmit an “on” signal for immune activation.
The most promising application involves combining anti-TIGIT agents with other checkpoint inhibitors, typically those targeting the PD-1/PD-L1 pathway. TIGIT and PD-1 are often co-expressed on exhausted T-cells, and their inhibitory mechanisms are complementary. Blocking both TIGIT and PD-1/PD-L1 simultaneously provides a dual release of inhibition, leading to a synergistic effect and a stronger anti-tumor response than blocking either pathway alone. This dual blockade significantly increases the production of pro-inflammatory cytokines, such as Interferon-gamma, necessary for effective tumor cell killing.
Current Clinical Development and Trial Results
The rationale for dual TIGIT and PD-1 blockade has propelled several anti-TIGIT agents into late-stage clinical development. Tiragolumab and vibostolimab are advanced antibodies explored in combination with anti-PD-1 or anti-PD-L1 therapies. Early studies showed that anti-TIGIT monotherapy yielded minimal clinical activity, confirming that combination with another checkpoint inhibitor is necessary for patient benefit.
Initial promising data came from the Phase II CITYSCAPE trial in non-small cell lung cancer (NSCLC) patients with high PD-L1 expression. The combination of tiragolumab and an anti-PD-L1 agent resulted in higher objective response rates and improved progression-free survival compared to the anti-PD-L1 agent alone. This suggested the dual approach benefits this specific patient population.
However, the path to regulatory approval has seen mixed results in subsequent large-scale Phase III trials. The SKYSCRAPER-02 trial in small cell lung cancer (SCLC) did not meet its primary endpoints for progression-free or overall survival, showing no benefit over the control arm. Some late-stage trials have been halted due to lack of efficacy or a higher incidence of immune-related adverse events. Despite these setbacks, ongoing Phase III trials continue to investigate the combination in other settings, including NSCLC, melanoma, and gastrointestinal cancers. Research now focuses on identifying specific tumor types and patient biomarkers that predict a positive response to TIGIT blockade.
Safety Profile and Administration
Anti-TIGIT drugs are administered via intravenous infusion, often following the dosing schedules of established checkpoint inhibitors (every two or three weeks). As a single agent in clinical trials, anti-TIGIT antibodies are well-tolerated, with reported side effects being mild to moderate. The most frequent adverse events include fatigue and pruritus (itching), common manifestations of immune activation.
When combined with PD-1 inhibitors, the overall safety profile remains manageable and consistent with established immunotherapy combinations. The main safety concern is immunotherapy-related adverse events (irAEs), which occur when the activated immune system targets healthy organs and tissues. These irAEs can affect various organ systems, causing inflammation in the skin (rash), colon (colitis), or endocrine glands (endocrinopathies).
Some large-scale trials have reported a slightly increased rate of immune-mediated adverse events compared to PD-1 monotherapy. Patient eligibility increasingly relies on biomarker testing, particularly PD-L1 expression levels, to identify those most likely to benefit from dual inhibition. Early recognition and prompt intervention, often using immunosuppressive drugs like corticosteroids, are paramount for safely managing these complications.