MISP (Mitotic Spindle Positioning) is a multifunctional protein that regulates both cell division and cancer-related processes. Primarily, MISP controls mitotic spindle orientation by stabilizing cortical and astral microtubule attachments through dynactin distribution at the cell cortex in a PLK1-dependent manner 1. Beyond mitosis, MISP plays critical roles in cell migration and adhesion dynamics. In cancer biology, MISP exhibits oncogenic functions. In gastric cancer, HER2 activation drives a SHCBP1-PLK1-MISP axis where PLK1 phosphorylates MISP to promote mitosis and tumorigenesis; this pathway impairs trastuzumab sensitivity, suggesting MISP inhibition as a therapeutic strategy 1. In intrahepatic cholangiocarcinoma, MISP upregulation correlates with increased lymphatic invasion, tumor progression, and motility through suppression of E-cadherin adherens junctions 2. Mechanistically, MISP localizes to cell-cell junctions where it suppresses E-cadherin dimerization, compromising epithelial integrity. In non-small cell lung cancer, MISP suppresses ferroptosis—a regulated cell death form—by binding MST1/2 kinases, inhibiting their autophosphorylation and sustaining YAP activation through Hippo pathway inhibition 3. This MISP-YAP feedback loop increases SLC7A11 expression, protecting cells from ferroptosis and promoting proliferation. MISP upregulation in NSCLC tissues correlates with treatment resistance and poor prognosis, positioning MISP as a potential therapeutic target for overcoming cancer cell death resistance.