The mitochondrial enigma: Deciphering mechanisms and identifying drug targets in polyploid giant cancer cells

Polyploid giant cancer cells (PGCCs) are the major driver of tumor recurrence, drug resistance, stemness, and are a significant obstacle in cancer therapy. These highly unstable cells form via mitotic slippage, failed cytokinesis, or cell fusion, and are implicated in chemotherapy-induced senescence. The survival and proliferation of PGCCs are critically dependent on altered mitochondrial dynamics and physiology, which includes a shift towards hyperfusion and asymmetric fission. PGCCs possess a higher mitochondrial content, indicating increased biogenesis to support their high metabolic demand, which is often met through glycolysis. After chemotherapy, these cells can bypass senescence to produce aggressive, proliferative progeny with enhanced stemness. This review documents the profound link between mitochondrial dynamics and the formation of PGCCs, their acquired drug resistance, and ability to drive tumor relapse. We propose that targeting mitochondrial dynamics and physiology offers a promising therapeutic strategy to combat PGCCs, providing a novel approach for next-generation personalized and precision cancer care.