fig1

Figure 1. Created with BioRender.com. (A) Mechanism of action of PARP inhibitors. PARP inhibitors trap PARP at the sites of single-strand DNA breaks. Ongoing replication forks clash with PARP-DNA complexes resulting in stalling of the replication forks and generation of double-stranded DNA breaks, which in the context of HRD are repaired through low-fidelity pathways, resulting in genomic instability and cellular death. (B) DNA damage drives inflammatory signaling, stimulating infiltration of innate immune cells such as macrophages and neutrophils, and it can make cells more visible and susceptible to killing by T cells and NK cells. In the context of HRD, PARP inhibitors can upregulate PD-L1 expression and induce cytotoxic T-cell recruitment, which is mediated through cGAS/STING pathway activation. (C) PD-1 signaling negatively regulates T-cell mediated immune response. PD-1 or PD-L1 inhibitors blocks PD-1/PD-L1 interaction, which facilitates an immune response that results in tumor cell kill. Cgas: Cyclic GMP-AMP synthase; HRD: homologous recombination deficiency; IL6: interleukin 6; IRF3: interferon regulatory factor 3; NF-B: nuclear factor-B; NK cell: natural killer cell; PARP: poly(ADP-ribose) polymerase; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; STING: stimulator of interferon genes; TBK1: TANK-binding kinase 1; TCR: T-cell receptor; TNFα: tumor necrosis factor α.