NEK2 is a serine/threonine kinase localized to the nucleus and cytoplasm that regulates critical cell cycle and centrosome processes 1. Primary functions include controlling centrosome duplication, spindle assembly, and chromosome 1 2. Beyond mitotic regulation, NEK2 phosphorylates PD-L1 at residues T194/T210 in the endoplasmic reticulum lumen, stabilizing PD-L1 and preventing its ubiquitin-proteasome degradation 3. NEK2 also regulates sphingolipid biosynthesis by controlling serine palmitoyl-CoA transferase activity in tumor-associated macrophages 4. NEK2 overexpression is strongly associated with poor prognosis across multiple solid tumors 5, with elevated expression linked to chr1 instability, aneuploidy, and centrosome amplification 1. In pancreatic cancer, NEK2 promotes immune evasion by maintaining PD-L1 stability, reducing lymphocyte infiltration 3. In hepatocellular carcinoma, NEK2-mediated sphingolipid synthesis in macrophages creates immunosuppression and confers checkpoint inhibitor resistance 4. NEK2 is implicated in drug resistance mechanisms, including trastuzumab resistance in breast cancer 2 and bortezomib resistance in multiple myeloma, where ammonium stabilizes NEK2 protein 6. NEK2 overexpression independently predicts adverse overall survival (HR=1.66) and disease-free survival (HR=2.00) 5. Small-molecule NEK2 inhibitors show therapeutic promise by suppressing PD-L1 expression, enhancing anti-tumor immunity, and reversing drug resistance 34.