The Sleeping Giant: Metabolism and Autophagy in the Generation and Survival of Dormant Polyploid Giant Cancer Cells

ABSTRACT A major limitation in preventing cancer relapse is our incomplete understanding of therapy resistance and tumor dormancy, including the role of therapy‐induced polyploidy in generating rapidly proliferating progeny that repopulate the tumor. In this context, polyploid giant cancer cells (PGCCs) are a unique subpopulation traditionally considered terminally senescent due to large size, abnormal DNA content, and inability to undergo mitosis. However, compelling evidence shows that PGCCs generate progeny via amitotic mechanisms (neosis), producing highly proliferative, chemo‐resistant tumor‐initiating cells that drive cancer relapse. Although metabolic adaptations and autophagy support PGCC formation and survival, the mechanisms underlying these processes and their contribution to tumor relapse remain poorly understood. This review explores the complex interplay between autophagy and metabolic adaptations in PGCCs, emphasizing their role in PGCC formation, long‐term survival and dormancy, and in the generation of amitotic progeny that drive tumor regrowth and cancer relapse. Mechanistic insights into how autophagy and metabolic plasticity enable PGCCs to withstand stress, maintain energy homeostasis, and escape therapy are highlighted. Additionally, we discuss therapeutic approaches targeting PGCCs by disruption of autophagy and metabolic pathways, evaluating their potential to impair progeny formation, overcome therapy resistance, and prevent cancer recurrence.