The immune checkpoint blockade (ICB) therapy has achieved a remarkable clinical benefits in patients with different malignancies by boosting the power of host immunity in cancer cell elimination. However, they are effective only in distinct patient subsets or result in the emergence of drug resistance due to a special differentiation state known as T-cell exhaustion. Therefore, the molecular mechanisms of resistance to ICB therapy need to be further investigated to design the potential combination strategies of immunotherapy. Exhausted T-cells undergo metabolic insufficiency with altered signaling cascades, and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to ICB therapies. How epigenetic and metabolic changes affect T-cell exhaustion remains unclear. We have identified through the analysis of the TCGA dataset that more than half of melanomas (cutaneous, uveal and acral subtypes) overexpress several epigenetic modulators such as EHMT2, BRD2 and SIRT5. This overexpression leads to immunosuppression, and are novel targets that can be inhibited to improve outcomes for melanoma patients by boosting ICB response. We demonstrate that inhibition of EHMT2 leads to a significant cell death in melanoma cell lines (cutaneous, uveal and acral subtypes), but not in normal melanocyte in vitro. In vivo studies revealed that EHMT2 inhibition led to a dramatic reduction in tumor growth, while boosting the efficacy of the ICB therapy in an anti-PD1-refractory tumour model in vivo. We found a strong inverse correlation between the transcript level of epigenetic modifiers (EHMT2, BRD2 and SIRT5) and the T-cell gene signature, suggesting the potential of reinvigorating T-cells by inhibiting these epigenetic modulators. These data provide a compelling evidence that epigenetic modifiers act as barrier to immune cell function, and efficiently targeted to boost anti-tumour T-cell function in improving melanoma patient outcomes.