Etiology of polyploid giant cancer cells: a new frontier in cancer biology

Polyploid giant cancer cells (PGCCs) are a distinct subpopulation of tumor cells characterized by enlarged morphology, increased nuclear content, and stem cell-like plasticity. Once considered senescent or non-functional, PGCCs are now recognized as critical drivers of tumor progression, metastasis, therapeutic resistance, and relapse. Their formation can be triggered by various stresses, including chemotherapy, radiotherapy, targeted therapies, as well as by other conditions such as endoplasmic reticulum (ER) stress or hypoxia. Mechanistically, PGCCs arise through processes such as endoreplication, mitotic slippage, cell fusion, and failed cytokinesis, which enable cells to escape mitotic catastrophe and transition into a polyploid state. Under therapeutic stress, PGCCs can persist by adopting a dormant or quiescent phenotype and later resume proliferation through neosis, characterized by asymmetric cytokinesis, generating daughter cells with enhanced migratory, invasive, and tumor-initiating capabilities. These progenies, along with the PGCCs themselves, frequently exhibit cancer stem cell (CSC)-like traits and undergo epithelial-mesenchymal transition (EMT), contributing to tumor heterogeneity and plasticity. Key signaling pathways implicated in PGCC biology include IL-6/IL-6R signaling, unfolded protein response (UPR), impaired p53 pathway, Aurora kinase B (AURKB) inhibition, and activation of the PLK4/CDC25C axis. PGCCs have also been shown to promote angiogenesis, induce therapy resistance, and evade immune surveillance. Clinically, elevated PGCC levels correlate with poor prognosis and resistance across multiple cancer types, including breast, colorectal, lung, ovarian, and so on. Given their unique properties and clinical relevance, PGCCs represent a promising frontier in cancer biology with the potential to overcome therapeutic resistance and prevent tumor recurrence through targeted interventions. This review seeks to elucidate the role of PGCCs across multiple cancer types and highlights their emerging potential as novel targets for future cancer therapies.