Nuclear-Cytoplasmic Axis in Cancer: From Protein Mislocalization to Anticancer Drug Resistance

Nucleocytoplasmic transport (NCT) regulates the spatial distribution of proteins and RNA between the nucleus and cytoplasm. NCT dysregulation can mislocalize tumor suppressors, DNA-repair factors, transcription factors, and drug targets in cancer. In this review, we conceptualize NCT-dependent protein mislocalization as a spatial regulatory framework for anticancer drug resistance, rather than as a catalogue of transport components. We systematically discuss how nuclear pore complex (NPC) remodeling, transport-receptor imbalance, post-translational modification (PTM)-regulated cargo routing, signaling-NCT crosstalk, nuclear localization signal/nuclear export signal (NLS/NES) alterations, and tumor microenvironmental pressures jointly drive aberrant nucleocytoplasmic distribution. These processes can further regulate apoptosis, DNA-damage repair, oncogenic transcription, oxidative stress adaptation and drug-target accessibility, which ultimately promote drug tolerance and therapeutic resistance. We further distinguish clinically validated mechanisms from preclinical phenotypes and correlative observations. At present, the most advanced therapeutic evidence mainly supports exportin 1/chromosome region maintenance 1 (XPO1/CRM1) inhibition, particularly selinexor in selected hematologic malignancies; in contrast, strategies targeting the NPC, importins, PTM pathways, microenvironmental cues, or localization signals remain largely investigational. By integrating mechanistic, preclinical, translational, and clinical evidence, this review aims to synthesize current evidence on NCT-dependent protein mislocalization as a resistance-relevant axis and to highlight the need for cargo-specific biomarkers and rational combination strategies to translate this biology into anticancer therapy.