CTLA4 and melanoma: While the use of epigenetic modifiers as single-agent therapy has not provided significant results for melanoma patients, preliminary results from clinical studies exploring the combination of epigenetic modifiers and ICIs appears to be scant, so far and many challenges remain including i) differences in clinical outcomes between different dosing regimens and types of immunotherapeutic backbones (anti-PD-1 vs anti-CTLA-4 vs anti-PD-1 plus anti-CTLA-4), ii) high rates of grade 3–4 adverse events; and iii) the long-term clinical benefits.