TIGIT (T-cell immunoreceptor with Ig and ITIM domains) has emerged as a promising target in cancer immunotherapy due to its critical role in suppressing T-cell-mediated anti-tumor immune responses. TIGIT, a co-inhibitory receptor, is expressed on various immune cells, including CD8+ T cells, NK cells, and regulatory CD4+ T cells. It primarily binds to CD155 (poliovirus receptor, PVR), which is overexpressed in several types of cancer, including melanoma, colon cancer, lung adenocarcinoma, and pancreatic cancer. This interaction inhibits immune cell activation, leading to reduced anti-tumor immunity. Given the high expression of TIGIT in many malignancies, it has become an attractive target for cancer immunotherapy.
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Research has shown that blocking TIGIT can enhance the anti-tumor functions of CD8+ T cells and NK cells, improving tumor clearance and survival rates in preclinical models. Anti-TIGIT antibodies have demonstrated promising results in boosting immune responses, particularly when combined with other immune checkpoint inhibitors, such as PD-1/PD-L1 blockers. These combination therapies are being actively explored to overcome the limitations of current immune checkpoint inhibitors, which do not work for all patients and can cause severe immune-related adverse events.
TIGIT’s therapeutic potential is attracting considerable interest from pharmaceutical companies, and as of early 2025, over 15 anti-TIGIT antibodies are in various stages of clinical and preclinical development. Among the most advanced candidates are Ociperlimab (by BeiGene), and Domvanalimab (by Arcus Biosciences). Notably, Tiragolumab (developed by Genentech) was the first anti-TIGIT antibody to receive breakthrough therapy designation from the U.S. FDA, underlining its potential as a key player in immuno-oncology. It works by blocking TIGIT’s interaction with CD155, thereby enhancing immune responses, particularly in combination with PD-L1 inhibitors. The combination of Tiragolumab and PD-L1 blockade has shown synergistic effects in clinical trials, suggesting it could significantly improve anti-tumor immunity.
In addition to monospecific antibodies, the development of bispecific antibodies targeting both TIGIT and PD-L1 has garnered significant attention. These bispecific antibodies are designed to engage multiple immune checkpoints simultaneously, aiming to enhance the overall immune response. For example, AGEN1777, developed by Agenus Therapeutics, is a TIGIT bispecific antibody that shows high specificity for both TIGIT and CD96, demonstrating superior anti-tumor activity in preclinical models compared to single-agent TIGIT or CD96 inhibitors.
Despite the promising results in preclinical and early clinical trials, the success of anti-TIGIT therapies hinges on the identification of reliable biomarkers to predict patient response. Not all patients will benefit from these treatments, and determining the right subset of patients who will respond to TIGIT blockade remains a critical challenge. As the clinical pipeline matures, identifying such biomarkers will be essential to maximize the therapeutic potential of TIGIT-targeted therapies.
As of January 2025, no anti-TIGIT therapy has been approved for commercial use, but the progress made in clinical trials and the significant interests from the pharmaceutical industry indicate that the first approvals could be forthcoming in the next few years. The success of anti-TIGIT therapies, particularly in combination with PD-1/PD-L1 inhibitors, could open new avenues for treating cancers that are resistant to current therapies. As the clinical landscape evolves, the development of biomarkers and patient selection strategies will be key to unlocking the full potential of TIGIT-targeted treatments in cancer therapy.