Cell cycle regulation plays a critical role in cell growth and proliferation. Three important groups of molecules are involved in this process: Cyclin-Dependent Kinases (CDKs), Cyclins, and Cyclin-Dependent Kinase Inhibitors (CKIs). p27 is a family member of cyclin-Dependent Kinase Inhibitors which can stop cells in certain phases until receive the mitogenic signals. Recent studies have shown that subcellular localization is significant for its function and degradation. Additionally, the post-translational modifications will determine the fate of p27. In this study, we aim to verify the role of phosphorylation at Serine 10 site and nuclear import signal for p27. Also, we find a special property of cancer cells to sense and respond to external cellular stresses. We find that in cancer cells the p27 will export the nucleus and degrade in the tumor microenvironment (TME) like conditions such as high temperature, acid, and hypoxia. Our findings provide a novel and promising direction for cancer treatment by blocking the p27 nuclear export during tumor progression process.