The activity of CUL5 is highly dependent on NEDD8-mediated neddylation, and its dysregulation indirectly influences tumor cell proliferation, apoptosis, metabolic reprogramming, angiogenesis, and the immune microenvironment by modulating key signaling pathways such as NOXA, mTORC, TRAF6/NF-κB, and JAK/STAT. This evidence concerns the gene PMAIP1 and neoplasm.