PTEN is a dual-specificity phosphatase that functions as a critical tumor suppressor through multiple mechanisms. Cytoplasmic PTEN antagonizes the PI3K/AKT/mTOR signaling pathway to suppress cellular proliferation and survival 1. Beyond cytoplasmic functions, PTEN exhibits important nuclear roles in genome maintenance, DNA repair, cell-cycle control, and chr10 remodeling through interactions with histone H1 and regulation of gene expression 23. PTEN also regulates angiogenesis by suppressing HIF-1α and the PI3K/AKT pathway, with downregulation occurring in 30-40% of melanomas 4. PTEN regulation involves complex post-translational modifications. Neddylation under high glucose conditions promotes nuclear accumulation of PTEN, which unexpectedly promotes cell proliferation by dephosphorylating FASN to enhance fatty acid synthesis—revealing a tumor-promoting role for nuclear neddylated PTEN 5. Ubiquitination and deubiquitination by enzymes like USP7, USP10, and USP13 dynamically regulate PTEN stability and subcellular localization 6. PTEN loss correlates with advanced disease, chemotherapy resistance, and poor survival across multiple cancers including lymphoma, hepatocellular carcinoma, and melanoma 17. Stromal PTEN inactivation additionally correlates with worse cancer outcomes, highlighting non-cell-autonomous tumor suppression 8. Germline PTEN mutations cause Cowden syndrome and related disorders with increased cancer susceptibility.