The recent developments of cancer immunotherapies that target immune checkpoint proteins are demonstrating durable clinical success for melanoma patients. However, a large proportion (60-70%) of patients do not respond to this treatment and therefore it is crucial to develop predictive biomarkers for the success of this therapy. Recent data from pre-clinical models and our own work suggest that distinct DNA methylation profiles of patients could potentially serve as a predictive biomarker. Based on epigenomic and immune gene-related profiles of responder and non-responder patients, we will develop a DNA methylation marker panel that predicts the likelihood of melanoma patients responding to immune checkpoint treatment. We will then perform functional assays and molecular editing of key loci to understand how exclusive DNA methylation changes in cells regulate immune checkpoint signalling. This work will contribute to selecting the best treatment option for patients, and also for developing new targets for epigenetic therapies.