Focus on TIGIT Immunotherapy

What Is Immunotherapy?

Many people with healthy immune systems still develop cancer. Sometimes the immune system doesn’t see the cancer cells as foreign because the cells aren’t different enough from normal cells, and sometimes the immune system recognizes the cancer cells, but the response might not be strong enough to destroy the cancer. Immunotherapy is a treatment approach that uses parts of your immune system to fight diseases such as melanoma by stimulating your own immune system to work harder or smarter to attack cancer cells.

Understanding Immune Checkpoints¹

Our immune system consists of a group of cells (T cells, B cells, natural killer cells) that defend the body against viruses and other pathogens. These immune cells can sometimes overreact and/or damage normal cells and lead to problems such as allergic reactions and auto-immune diseases. The immune system also recognizes and destroys abnormal cells, but some cells can remain and later develop into cancer.

Our immune system has “checkpoints” that regulate our immune response and ensure that healthy cells are not destroyed. In general, they work like this: Immune cells express immune checkpoint protein receptors that can recognize their counterparts (called ligands) on normal and tumor cells. If these receptors find their ligands and interact in a way similar to a lock and key mechanism, the checkpoint activates and starts shutting the immune response off. If these receptors do not find their ligands, the checkpoint is not activated, and the immune system launches an immune response.

These mechanisms are important for us to stay healthy because they allow the body to keep immune cells active when needed and to shut them off if they are activated inappropriately. Unfortunately, cancer cells exploit these mechanisms. Cancer cells often express the ligands of immune checkpoints, and when the receptors interact with them, the immune cells turn off instead of attacking the growing tumor.

When immune cells encounter melanoma cells, they may express a protein receptor called PD-1. In addition, melanoma tumor cells may express the ligand of PD-1—called PD-L1. If the PD-1 receptor interacts with the PD-L1 ligand, the immune checkpoint PD-1 is tricked into stopping the immune response and the cancer grows in an uncontrolled way. A protein called CTLA-4 may also be expressed when immune cells encounter melanoma cells, which also halts the immune response.

Checkpoint Inhibitor Therapies and Unmet Needs

Immunotherapies known as immune checkpoint inhibitors (ICIs) are designed to halt the activation of immune checkpoints and reinvigorate immune cells. Examples are ipilimumab (Yervoy), which blocks CTLA-4, and nivolumab (Opdivo) and pembrolizumab (Keytruda), which both block PD-1 on immune cells binding to PD-L1 on cancer cells.

Checkpoint inhibitor therapies have been a major advance for patients with melanoma. Recent long-term data show that the melanoma-specific survival rate at 10-years was 52% with nivolumab-plus-ipilimumab.² However, not all patients respond to immunotherapy and some initially respond but then develop resistance.² As a result, it is important to evaluate additional immune checkpoints as targets for therapies.

What is TIGIT and How Does it Work?

TIGIT, which refers to T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibition motif domain, is an emerging immune checkpoint target.³  The TIGIT receptor is located on the surface of immune cells called T cells and natural killer cells.³ When the TIGIT receptor binds to ligands, such as CD155, on tumor cells, anti-cancer immune responses are inhibited.³  This binding is analogous to a lock and key, with the receptor as the lock and the ligand as the key.

Importantly, researchers have observed an increase in expression of TIGIT in cancers such as melanoma, and this increase in expression is associated with poorer survival/outcomes.^3-5 Furthermore, research shows that advanced melanoma tumors that do not respond well to first-line immunotherapies have increased levels of the TIGIT ligand CD155.⁶ In addition, blocking TIGIT activity appears to increase tumor immune responses, and this provides the rationale for evaluating anti-TIGIT therapies.³

What Anti-TIGIT Immunotherapies are in Development?

Monoclonal antibodies are currently in development to inhibit TIGIT by blocking binding to ligands such as CD155. Some anti-TIGIT drug candidates further along in development include domvanalimab, ociperlimab, and tiragolumab.^7-9 Anti-TIGIT monotherapies have not been successful; however, combination approaches with anti-PD-1 therapies have shown promise.⁹

Recent data presented at the American Society of Clinical Oncology 2025 meeting from the NEOACTIVATE Arm C trial showed the efficacy of tiragolumab in combination with atezolizumab in Stage III melanoma.¹⁰ Patients with high-risk, operable Stage III melanoma were treated with tiragolumab in combination with the anti-PD-L1 monoclonal antibody atezolizumab followed by therapeutic lymph node dissection and adjuvant atezolizumab. Major pathologic responses were observed in 16 out of 34 (47.1 %) patients. According to the authors, the degree of pathologic response was similar but slightly lower than with nivolumab plus ipilimumab and nivolumab plus relatlimab. After 12 months, 73.3% of patients remained recurrence-free from melanoma and 86.0% of patients were surviving without distant metastases.These results encourage additional studies using anti-TIGIT agents in combination with other immunotherapies in clinical trials for melanoma.

Key Takeaways

Current immunotherapies are effective in melanoma; however, not all patients respond and some develop resistance. Additional immunotherapies, such as anti-TIGIT therapies, are under investigation, and recent results suggest that they may be a promising treatment option for patients in the future.

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References

1. He X, Xu C. Immune Checkpoint Signaling and Cancer Immunotherapy. Cell Res. 2020;30(8):660-669.
2. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med. 2025;392(1):11-22.
3. Tang W, Chen J, Ji T, Cong X. TIGIT, a novel immune checkpoint therapy for melanoma. Cell Death Dis. 2023;14(7):466.
4. Chauvin JM, Zarour HM. TIGIT in Cancer Immunotherapy. J Immunother Cancer. 2020;8(2):e000957.
5. Kamińska P, Buszka K, Galus Ł, et al. Circulating Melanoma Cell Numbers Correlate with TIGIT-Positive Cytotoxic T Cell Counts in Advanced-Stage Melanoma Patients. Cells. 2023;12(6):856. 
6. Lepletier A, Madore J, O’Donnell JS, et al. Tumor CD155 Expression Is Associated with Resistance to Anti-PD1 Immunotherapy in Metastatic Melanoma. Clin Cancer Res. 2020;26(14):3671-3681.
7. Dumbrava EE, Ben Haj Frej K, Sharon E, Tawbi H. Application and Expectations for Immune Checkpoint Blockade of LAG3 and TIGIT. Annu Rev Med. 2025;76(1):189-205. 
8. Rousseau A, Parisi C, Barlesi F. Anti-TIGIT Therapies for Solid Tumors: a Systematic Review. ESMO Open. 2023;8(2):101184.
9. Sundstrom EC, Huang X, Wiemer AJ. Anti-TIGIT Therapies: A Review of Preclinical and Clinical Efficacy and Mechanisms. Cancer Immunol Immunother. 2025;74(8):272.
10. Hieken TJ, Zahrieh D, Flotte TJ, et al. NeoACTIVATE Arm C: Phase II Trial of Neoadjuvant Atezolizumab and Tiragolumab for High-risk Operable Stage III Melanoma. Eur J Cancer. Published online August 6, 2025.