DNA polymerase θ (POLθ) plays a central role in microhomology-mediated end joining (MMEJ), an error-prone DSB repair pathway. Under normal conditions, MMEJ acts as a backup repair mechanism. However, in HRR-deficient tumors, reliance on POLlθ-driven MMEJ is markedly increased, making POLθ essential for cancer cell survival. Researchers from Astrazeneca plc reported the discovery and characterization of AZD-4956, a POLθ inhibitor that can be used in combination with PARP inhibitors and other DNA-damaging agents.