Polyploid giant cancer cells: Survival, progeny formation, and therapeutic targeting.

Polyploid giant cancer cells (PGCCs) are enlarged tumor cells with markedly increased genomic content that can arise or become enriched after therapeutic or microenvironmental stress. Some survive for prolonged periods and generate smaller daughter cells, but progeny formation does not invariably lead to sustained growth or inherited drug resistance. This review examines PGCC biology through three distinct outcomes: survival, progeny formation, and sustained progeny expansion. We integrate experimental and human evidence on these outcomes while distinguishing PGCC-specific findings from work on whole-genome doubling and related polyploid states. Apoptosis regulation, autophagy-lysosomal activity, and mitochondrial and redox adaptation support survival in defined models. Progeny formation involves nuclear reorganization, extracellular signaling, lipid metabolism, and membrane separation. The resulting progeny vary in proliferative capacity, genomic organization, and phenotypic plasticity, while giant cells and their progeny can influence stromal and immune responses. Human studies associate PGCC-related phenotypes with adverse pathology or outcomes, but their contribution to recurrent tumor lineages remains unresolved. Preclinical interventions act at different stages, from giant-cell establishment and survival to progeny release, progeny growth, and tumor-supportive signaling. Their effects therefore depend on treatment context and timing, and cannot be inferred from short-term changes in PGCC abundance alone. Linking these stage-specific responses to sustained tumor control is central to evaluating PGCC-directed therapy.