Inhibition of replication origins and ATR synergistically activates the innate immune system in cancer cells

In cancer cells, maintaining an adequate number of active replication origins is crucial for successful DNA replication. Our study explores a novel strategy to enhance the effectiveness of ATR inhibitors in ovarian cancer treatment by targeting replication origins. We demonstrate that inhibiting replication origin activation and reducing their number sensitizes ovarian cancer cells to ATR inhibition, leading to increased genomic instability. This combinatorial approach activates the innate immune system through the cGAS-STING pathway, potentially enhancing the immune response within tumors. Importantly, this effect is not observed in normal cells, highlighting its cancer-specific potential. Our findings offer a promising avenue for improving ATR inhibitor therapy and leveraging innate immunity in cancer treatment.