A combined targeting of CTLA-4 and PD-1 in treatment-naïve patients with melanoma with BrM demonstrated a 45–55% intracranial response rate, which was significantly higher as compared with the anti-PD-1 monotherapy (∼25% intracranial response rate).6 7 However, the response rate is significantly lower in patients with symptomatic BrM and the responses are rarely durable.8 9 It is therefore important to understand what drives the intracranial efficacy of immune checkpoint blockade (ICB), to enable the development of strategies for enhanced ICB activity in BrM. Here, CTLA4 is linked to melanoma.