Inpp4b, or inositol polyphosphate 4-phosphatase type II, is an emerging dual-role cancer driver gene. It is primarily known as a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. By hydrolysing PtdIns(3,4)P2, it negatively impacts PI3K/AKT signalling, which is involved in cell proliferation, survival, migration, and metabolism [1].

In a genetically engineered triple-negative breast cancer (TNBC) mouse model with Inpp4b deficiency, there was a dose-dependent increase in tumor incidence, supporting its role as a tumor suppressor in TNBC. Inpp4b deficiency led to increased PI(3,4)P2 levels in endocytic vesicles, delayed degradation of EGFR and MET, and enhanced RTK recycling, thus promoting tumorigenesis [5]. In glioma, overexpression of Inpp4b restrained cell proliferation, migration, apoptosis resistance, PD-L1 expression, and T cell suppression by glioma cells, while silencing had opposite effects, with Inpp4b inhibiting these processes via down-regulating PI3K/AKT signalling [4]. In pancreatic ductal adenocarcinoma (PDAC), Inpp4b overexpression was associated with PDAC progression, promoting lysosomal exocytosis and enhancing migratory and invasive potential [2]. In HER2 + breast cancer, Inpp4b expression was lower, and overexpression inhibited cell proliferation, migration, and growth of xenografts, while depletion promoted epithelial-mesenchymal transition (EMT) [3].

In conclusion, Inpp4b has complex functions in various cancer types, mainly through its regulation of the PI3K/AKT signalling pathway. Gene knockout mouse models have been crucial in revealing its role as a tumor suppressor in TNBC and glioma, and its paradoxical oncogenic role in PDAC and some other malignancies. Understanding Inpp4b's functions provides insights into cancer development mechanisms and potential therapeutic targets.