SPOP (speckle type BTB/POZ protein) functions as a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex that mediates polyubiquitination of diverse target proteins 1. SPOP catalyzes both degradative and non-degradative ubiquitination of substrates including androgen receptor (AR), BRD4, PD-L1, c-Myc, and p62/SQSTM1, regulating pathways critical for cell proliferation, DNA repair, and immune surveillance 1. Mechanistically, SPOP binding promotes proteasomal degradation of most targets, though some substrates undergo non-degradative modification affecting their activity 1. SPOP's role in cancer is context-dependent: it functions as a tumor suppressor in prostate and endometrial cancers, where mutations impair substrate recognition and polyubiquitination 12. SPOP mutations in prostate cancer promote p62-dependent autophagy and Nrf2 activation in a dominant-negative manner, conferring oncogenic advantage 3. Conversely, SPOP is overexpressed in renal cell carcinoma, acting as an oncoprotein 1. In bladder cancer, SPOP-mediated LATS1 degradation suppresses Hippo signaling 4. Loss-of-function SPOP mutations compromise PD-L1 degradation, increasing immune checkpoint expression and reducing anti-tumor immunity 5. SPOP mutations define a molecular subtype in primary prostate cancer associated with elevated AR signaling 2. Understanding SPOP's substrate specificity and regulation offers therapeutic opportunities for SPOP-mutated cancers.