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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\u2010resistant tumor\u2010initiating 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\u2010term 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.<\/jats:p>","DOI":"10.1002\/mco2.70873","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:44:35Z","timestamp":1789969475000},"source":"Crossref","is-referenced-by-count":0,"title":["The Sleeping Giant: Metabolism and Autophagy in the Generation and Survival of Dormant Polyploid Giant Cancer Cells"],"prefix":"10.1002","volume":"7","author":[{"given":"Silvia","family":"Guil\u2010Luna","sequence":"first","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC)  Cordoba Spain"},{"name":"University of Cordoba  Cordoba Spain"},{"name":"Reina Sofia University Hospital  Cordoba Spain"},{"name":"Cancer Network Biomedical Research Centre (CIBERONC)  Madrid Spain"},{"name":"Department of Anatomy and Comparative Pathology and Toxicology Faculty of Veterinary Medicine of C\u00f3rdoba University of C\u00f3rdoba  C\u00f3rdoba Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Teresa","family":"S\u00e1nchez\u2010Montero","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC)  Cordoba Spain"},{"name":"University of Cordoba  Cordoba Spain"},{"name":"Reina Sofia University Hospital  Cordoba Spain"},{"name":"Cancer Network Biomedical Research Centre (CIBERONC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"D\u00edaz\u2010Chac\u00f3n","sequence":"additional","affiliation":[{"name":"Maimonides Biomedical Research Institute of Cordoba (IMIBIC)  Cordoba 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