In this study, we unveils the regulation mechanism underlying the cytoplasmic p53 sequestration of NB cells, by which TSPYL5 drives G3BP1 (G3BP stress granule assembly factor 1)/RanBP2 (RAN binding protein 2)/SUMO (small ubiquitin-related modifier)-mediated p53 sumoylation, enhancing p53 nuclear export signal and inhibiting its tumor suppressor activity. Here, TP53 is linked to neuroblastoma.