Association of EYS mutations with immune checkpoint inhibitor outcome and response in melanoma and non-small cell lung cancer

Immunotherapy with immune checkpoint inhibitor (ICI) improved outcomes in advanced/metastatic melanoma and non-small cell lung cancer (NSCLC), but only a subset of patients benefited significantly. Existing biomarkers like tumor mutational burden (TMB) and microsatellite instability (MSI) had limitations, prompting the search for novel biomarkers. EYS , which is primarily involved in retinal photoreceptor function and visual system development, had not been explored for its potential role in predicting ICI therapy responses. In this study, data on pretreatment mutations, ICI treatment information, and clinicopathological data of 631 melanoma samples and 109 NSCLC samples were integrated. Meanwhile, immune infiltration and signaling pathway enrichment associated with EYS mutation were evaluated based on transcriptome gene expression profiles. In the melanoma cohort, EYS mutations were associated with significantly improved ICI outcome (HR: 0.62, 95%CI: 0.45–0.86, P  = 0.004) and response rate (43.4% vs. 28.6%, P  = 0.004). The findings were corroborated in NSCLC samples, where patients with EYS mutations exhibited a significantly better prognosis under ICI therapy (HR: 0.26, 95% CI: 0.08–0.83, P  = 0.023) and a higher response rate (75.0% vs. 30.0%, P  = 0.004). Further analysis showed that EYS mutations were associated with elevated tumor mutational burden, enhanced immune cell infiltration, and activation of immune-related signaling pathways. Our results showed that EYS mutation was associated with better ICI response, which provided a theoretical basis for clinical tumor immunotherapy strategy development and provided a possible molecular marker for assessing treatment response.