Centrosome de-clustering of cancer cells induces cGAS-STING-mediated innate immunity of tumor-associated tumor cells in response to irradiation.

Although radiotherapy (RT) increases the extra centrosomes of cancer cells compared to normal cells, centrosome clustering of cancer cells with amplified centrosomes ensures bipolar mitosis for cell proliferation in response to RT. Recent evidence suggests that centrosome clustering is a tumor-selective target for improving RT in breast cancer cells. However, whether centrosome de-clustering is involved in the activation of innate immunity in response to RT remains unknown. In this study, we showed that centrosome de-clustering of irradiated cancer cells modulates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated innate immunity in monocytes and macrophages after co-culture. Centrosome de-clustering intensifies mitotic abnormalities and cytosolic dsDNA in breast cancer cells in response to irradiation. Unexpectedly, centrosome de-clustering did not modulate the cGAS-STING signaling pathway in irradiated breast cancer cells. Importantly, centrosome de-clustering activated the cGAS-STING signaling pathway in human monocytes and mouse macrophages after co-culture with irradiated breast cancer cells. Thus, our data provide the first evidence that centrosome de-clustering of irradiated breast cancer cells induces innate immunity in tumor-associated immune cells.