Anti-TIGIT Immunotherapy in Melanoma

Checkpoint Inhibitor Therapies and Unmet Needs

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.¹ However, not all patients respond to immunotherapy and some initially respond but then develop resistance.¹ 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.² The TIGIT receptor is located on the surface of immune cells called T cells and natural killer cells.² When the TIGIT receptor binds to ligands, such as CD155, on tumor cells, anti-cancer immune responses are inhibited.² 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.^2-4 Furthermore, research shows that advanced melanoma tumors that do not respond well to first-line immunotherapies have increased levels of the TIGIT ligand CD155.⁵ In addition, blocking TIGIT activity appears to increase tumor immune responses, and this provides the rationale for evaluating anti-TIGIT therapies.²

Anti-TIGIT Therapies 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.^6-8 Anti-TIGIT monotherapies have not been successful; however, combination approaches with anti-PD-1 therapies have shown promise. ⁸

Recent Data in Melanoma

Recent data presented from the NEOACTIVATE Arm C trial presented at the American Society of Clinical Oncology 2025 meeting and also just published showed the efficacy of tiragolumab in combination with atezolizumab in Stage III melanoma.⁹

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 tumor types such as 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.

Additional Reading

Dummer R, Robert C, Scolyer RA, et al. Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial. Nat Med. 2025 Jan;31(1):144 151. https://pmc.ncbi.nlm.nih.gov/articles/PMC11750705/

Kreidieh FY, Tawbi HA. The introduction of LAG-3 checkpoint blockade in melanoma: immunotherapy landscape beyond PD-1 and CTLA-4 inhibition. Ther Adv Med Oncol. 2023;15:17588359231186027. https://pmc.ncbi.nlm.nih.gov/articles/PMC10357068/

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References

1. 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.
2. Tang W, Chen J, Ji T, Cong X. TIGIT, a Novel Immune Checkpoint Therapy for Melanoma. Cell Death Dis. 2023;14(7):466.
3. Chauvin JM, Zarour HM. TIGIT in Cancer Immunotherapy. J Immunother Cancer. 2020;8(2):e000957.
4. 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. 
5. 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.
6. 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. 
7. Rousseau A, Parisi C, Barlesi F. Anti-TIGIT Therapies for Solid Tumors: a Systematic Review. ESMO Open. 2023;8(2):101184.
8. 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.
9. 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.