Scientists have identified three immune-related genes that could help predict how aggressive skin melanoma becomes, and how well patients might respond to treatment.
In a new study, researchers investigated the roles of LAG-3, TIGIT and HAVCR2 in skin cutaneous melanoma (SKCM), one of the deadliest forms of skin cancer. Melanoma incidence and mortality continue to rise globally, despite major advances in immunotherapy.
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have transformed melanoma treatment. Drugs such as relatlimab, which blocks LAG-3, have shown promise when combined with PD-1 inhibitors. However, resistance to therapy and immune-related side effects remain significant challenges. Researchers are therefore searching for additional immune targets that could improve outcomes.
LAG-3 and TIGIT Identified as Predictors of Skin Melanoma Progression
Using large-scale bioinformatic analyses, the team examined gene expression, immune cell infiltration, mutation patterns and DNA methylation in melanoma samples. They found that LAG-3, TIGIT and HAVCR2 were significantly overexpressed in melanoma tissue compared with normal skin. Expression levels were even higher in metastatic tumours than in primary tumours.
Surprisingly, higher expression of these genes was associated with improved overall survival. Patients whose tumours showed elevated LAG-3 or TIGIT levels had better outcomes, even after adjusting for age, cancer stage and measures of immune and stromal cell presence in the tumour microenvironment. HAVCR2 was also linked to survival, but it did not retain independent prognostic significance after statistical correction.
Immune-high Tumours Show Strongest Survival Associations
The researchers found that tumours with high expression of these genes also showed increased immune cell infiltration, particularly T cells and macrophages, and higher immune and stromal scores. This suggests that the genes may reflect a more active anti-tumour immune response. Prognostic effects were strongest in tumours already classified as “immune-high.”
The study also highlighted epigenetic regulation as a potential mechanism. Promoter hypermethylation was associated with reduced gene expression, pointing to DNA methylation as a possible modulator of immune activity in melanoma.
The findings suggest that LAG-3 and TIGIT, in particular, could serve as prognostic biomarkers and future immunotherapy targets. Researchers say further clinical studies are needed to determine whether combining therapies against these checkpoints with existing treatments could enhance survival for patients with advanced melanoma.
Reference
Vryza P et al. Predicting skin melanoma progression via LAG-3, TIGIT and HAVCR2. Funct Integr Genomics. 2026;26:53.
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