This study investigates the role of transient loss of Polycomb group (PcG) proteins in inducing an epigenetic cancer fate in Drosophila. The authors demonstrate that a transient perturbation of transcriptional silencing mediated by PcG proteins is sufficient to induce an irreversible switch to a cancer cell fate, characterized by the derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signaling pathway and zfh1, the fly homologue of the ZEB1 oncogene. The study shows that this epigenetic perturbation can lead to tumorigenesis without the presence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to the inheritance of altered cell fates. The authors further explore the chromatin and transcriptional changes associated with this process, identifying specific transcription factor binding motifs that may contribute to the maintenance of an active state at irreversible genes. Finally, they demonstrate that the tumorigenic potential of these epigenetically initiated cancers (EICs) is autonomous, increases over time, and can propagate months after the removal of the perturbation. This work highlights the importance of epigenetic mechanisms in cancer initiation and progression, providing insights into the potential role of epigenetic reprogramming in tumour plasticity and metastasis.This study investigates the role of transient loss of Polycomb group (PcG) proteins in inducing an epigenetic cancer fate in Drosophila. The authors demonstrate that a transient perturbation of transcriptional silencing mediated by PcG proteins is sufficient to induce an irreversible switch to a cancer cell fate, characterized by the derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signaling pathway and zfh1, the fly homologue of the ZEB1 oncogene. The study shows that this epigenetic perturbation can lead to tumorigenesis without the presence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to the inheritance of altered cell fates. The authors further explore the chromatin and transcriptional changes associated with this process, identifying specific transcription factor binding motifs that may contribute to the maintenance of an active state at irreversible genes. Finally, they demonstrate that the tumorigenic potential of these epigenetically initiated cancers (EICs) is autonomous, increases over time, and can propagate months after the removal of the perturbation. This work highlights the importance of epigenetic mechanisms in cancer initiation and progression, providing insights into the potential role of epigenetic reprogramming in tumour plasticity and metastasis.