Abstract
The epidermal growth factor receptor (EGFR) is a recognized target in tumor treatment. While there is significant focus on inhibiting membrane EGFR and its downstream signaling activation, the ectopic accumulation of EGFR, particularly nuclear EGFR (nEGFR), has been implicated in tumor-associated activities and associated with poor prognosis. Within the nucleus, nEGFR functions as a transcriptional regulator to modulate transcriptional landscape and exerts tyrosine kinase activity to phosphorylate nuclear proteins and subsequently influences DNA repair, cell cycle, proliferation, and resistance to radiotherapy and chemotherapy. The nuclear localization of EGFR involves the internalization, subcellular trafficking, and nuclear envelope shuttling of membrane EGFR. Given the challenges of delivering drugs to the nucleus for targeting nEGFR, understanding the molecules affecting the translocation process is crucial for novel insights. This review initially explores the association between nEGFR expression and clinical outcomes and then elucidates how nEGFR fulfills its regulatory role within the nucleus. Subsequently, the mechanisms governing EGFR nuclear translocation and potential therapeutic targets during this process are summarized, highlighting avenues to target nEGFR as an innovative strategy in tumor treatment.