PLK3 (polo-like kinase 3) is a serine/threonine protein kinase that functions as a tumor suppressor and stress response regulator. Unlike PLK1 which promotes oncogenesis, PLK3 acts as a tumor suppressor that is frequently downregulated in various cancers 1. In colon cancer, PLK3 mRNA levels are significantly reduced in tumors compared to normal mucosa, and ectopic expression of active PLK3 induces apoptosis in colon carcinoma cells 2. The protein plays critical roles in cell cycle regulation and stress responses, being rapidly activated by ionizing radiation, reactive oxygen species, hyperosmotic stress, UV irradiation, and hypoxia 1. PLK3 contributes to DNA damage response pathways and mediates apoptosis under cellular stress conditions 1. In prostate cancer, PLK3 is regulated by ALDH1A1 and ALDH1A3 in an androgen receptor and retinoid receptor-dependent manner, where it controls cell proliferation, migration, DNA repair, and radioresistance 3. PLK3 can also be modified by methylation, which affects its phosphorylation activity and downstream signaling through HIF1α pathways in chemoresistant breast cancer stem cells 4. Current PLK1 inhibitors in clinical development also target PLK2 and PLK3, which may complicate therapeutic outcomes since these kinases function as tumor suppressors 5.