Autophagy activation promotes the formation of dormant polyploid giant cancer cells via the AMPK-mTOR pathway

Dormant cancer cells that survive anti-cancer therapy can lead to cancer recurrence and disseminated metastases that ultimately prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCCs) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as clarified by our clinical data. We reported their biological properties including mitochondrial alterations and revealed that autophagy is a critical mechanism of PGCC induction, with the pharmacological or genetic inhibition of autophagy greatly impairing PGCC formation, significantly eliminating recurrence and metastasis, and improving survival in a mouse model. Mechanistically, we observed that chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Transcriptionally activated RIPK1 acts as a scaffold, promoting PGCC survival via the AMPK-mTOR pathway. Our findings suggest a therapeutic approach of targeting dormant PGCCs for cancer treatments.