The study investigates the role of mitotic progression following DNA double-strand breaks (DSBs) in the induction of inflammatory responses and the formation of micronuclei. Key findings include: 1. **Mitotic Progression and Micronuclei Formation**: Following DSBs, cells progress through mitosis, leading to the formation of micronuclei. These micronuclei serve as a repository for the pattern recognition receptor cGAS, which is crucial for activating inflammatory signaling. 2. **Inhibition of Mitotic Progression Impairs Inflammation**: Inhibiting mitotic progression, either by blocking mitotic entry or by deleting cGAS-STING components, impairs the activation of inflammatory pathways and interferon signaling. 3. **cGAS Relocalization to Micronuclei**: cGAS dynamically relocalizes to micronuclei following mitosis, during migration, and after Aurora B kinase inhibition. This localization is essential for the activation of inflammatory responses. 4. **Abscopal Response and STING Signaling**: In a murine melanoma model, the abscopal effect (tumor regression outside the irradiated field) is dependent on STING signaling. Loss of STING impairs the abscopal response and reduces overall survival. 5. **Model for Inflammatory Signaling**: The study proposes a model where imperfect cell cycle checkpoints allow cells to progress through mitosis, leading to the accumulation of micronuclei and subsequent activation of inflammatory signaling. These findings highlight the importance of mitotic progression and micronuclei in the delayed onset of inflammatory responses following genotoxic therapies, and suggest that modulating these processes could be a potential strategy to enhance the efficacy of combination therapies involving genotoxic agents and immune checkpoint blockade.The study investigates the role of mitotic progression following DNA double-strand breaks (DSBs) in the induction of inflammatory responses and the formation of micronuclei. Key findings include: 1. **Mitotic Progression and Micronuclei Formation**: Following DSBs, cells progress through mitosis, leading to the formation of micronuclei. These micronuclei serve as a repository for the pattern recognition receptor cGAS, which is crucial for activating inflammatory signaling. 2. **Inhibition of Mitotic Progression Impairs Inflammation**: Inhibiting mitotic progression, either by blocking mitotic entry or by deleting cGAS-STING components, impairs the activation of inflammatory pathways and interferon signaling. 3. **cGAS Relocalization to Micronuclei**: cGAS dynamically relocalizes to micronuclei following mitosis, during migration, and after Aurora B kinase inhibition. This localization is essential for the activation of inflammatory responses. 4. **Abscopal Response and STING Signaling**: In a murine melanoma model, the abscopal effect (tumor regression outside the irradiated field) is dependent on STING signaling. Loss of STING impairs the abscopal response and reduces overall survival. 5. **Model for Inflammatory Signaling**: The study proposes a model where imperfect cell cycle checkpoints allow cells to progress through mitosis, leading to the accumulation of micronuclei and subsequent activation of inflammatory signaling. These findings highlight the importance of mitotic progression and micronuclei in the delayed onset of inflammatory responses following genotoxic therapies, and suggest that modulating these processes could be a potential strategy to enhance the efficacy of combination therapies involving genotoxic agents and immune checkpoint blockade.