(A) In female melanoma patients, the hormone estrogen (red circles) activates the G-protein coupled estrogen receptor (GPER, light blue), which increases signaling through the kinase PKA and the transcription factor CREB. This leads to increased expression of another transcription factor MITF, which in turn switches on pigmentation genes (and other genes responsible for melanocyte differentiation). At the same time, PKA suppresses a third transcription factor c-Myc, meaning that it no longer inhibits the expression of the cell-surface proteins HLA (blue). The net result is the increased recognition of the melanoma by the immune system (T-cells, shown in green). (B) Men have less estrogen, and so the GPER is not activated and c-Myc levels are likely to be higher. The lack of active GPER means that the pigmentation genes are not as active as they are in females. The high levels of c-Myc also inhibit the production of HLA and activate the immune checkpoint activator PD-L1. Together these factors lead to the melanoma adopting a less differentiated state and to decreased immune function via T-cell inhibition.