A series of previous reports has elucidated the upstream mechanisms responsible for the activation of IRE1α-XBP1 and other UPR signal branches in tumor and other diseases, including mutated oncogenic drivers BRAF, c-myc28,29 and post-translational regulations.30–33 Nevertheless, the molecular linkage between the nutrient-responsive sirtuins family and the IRE1α-XBP1 axis of UPR in stressful TME and the implication in melanoma tumor biology remains elusive. This evidence concerns the gene ERN1 and melanoma.