Polyploid giant cancer cells: A novel target in future cancer therapy

Under intense therapeutic stress-including chemotherapy, radiotherapy, and targeted therapies-tumor cells can undergo ploidy reprogramming to generate polyploid giant cancer cells (PGCCs). Once largely overlooked, this rare but biologically distinctive tumor cell subpopulation has now been firmly implicated across multiple malignancies in therapy resistance, metastatic progression, and tumor relapse. PGCCs are characterized by striking morphological and genetic features, including extreme cellular enlargement, multinucleation or high-ploidy states, and profound genomic instability. Importantly, under stress conditions, PGCCs can undergo depolyploidization to produce progeny with enhanced adaptive fitness. This review systematically synthesizes the major mechanisms underlying PGCC formation, including endoreplication, mitotic slippage, cytokinesis failure, cell fusion, and entosis, highlighting their contextual cooperation and temporal continuity across diverse stress environments and genetic backgrounds. We further delineate the core functional roles of PGCCs in tumor biology, with a particular focus on their contributions to therapeutic tolerance, metastasis promotion, and cancer stem cell-like properties, and critically examine their intimate links to intratumoral heterogeneity and tumor evolutionary dynamics. Building on these insights, we evaluate emerging therapeutic strategies targeting PGCCs and discuss current methodological challenges and future directions in their detection, multi-omics characterization, and machine learning-assisted identification.Collectively, PGCCs represent a pivotal stress-adapted cellular state that drives ongoing tumor evolution under therapeutic pressure. A deeper mechanistic understanding of PGCC biology may provide a conceptual framework and novel intervention strategies to overcome cancer resistance and recurrence.