PRL3 overexpression in multiple cancers has pleiotropic effects, causing cells to acquire hallmark traits such as sustained proliferative signaling, replicative immortality, genome instability and mutation, resistance to cell death, angiogenesis etc. Recent findings have also expanded our knowledge of PRL3-mediated functions, including its endogenous function in regulating stem cell differentiation during development, and its influence on the TME. This evidence concerns the gene PTP4A3 and cancer.