Fig. 1

The homologous recombination (HR) repair deficiency represents an opportunity for a synthetic lethality approach through the use of PARP inhibitors (PARPi). The DNA methyltransferase inhibitors (DNMTi) enhance the cytotoxic effects of PARPi by increasing the PARP1 trapping at DNA. At the same time, the accumulation of DNA damage, as a consequence of cell’s inability to repair the DSBs, results in a high tumor mutational burden and tumor surface neoantigens load associated with increased infiltration of T lymphocyte into tumor microenvironment. These events trigger the compensatory upregulation of PD-1/PD-L1 pathway offering the possibility to use the immune checkpoint inhibitors in order to kill the cancer cells that elude the immune system. Thus, targeting the PD-1/PD-L1 pathway with immune checkpoint inhibitors may rappresent an attractive approach for treament of the tumor with defects of HR repair