Figure 2.

Combination strategy, specifically targeting vital resistance pathways that are likely to enhance the cytotoxicity of poly (ADP‐ribose) polymerase inhibitors (PARPi). Poly (ADP‐ribose) polymerase inhibitor therapy increases DNA damage, releases tumor antigens (neoantigens), and might also upregulate checkpoint proteins like programmed cell death ligand‐1 (PD‐L1). These PARPi‐induced changes are likely to prime tumors and render them sensitive to enhanced immunogenic cell death. However, PARPi and checkpoint inhibitors are unlikely to have any effect on epithelial‐mesenchymal transition (EMT) or cancer stem cells (CSCs). Many epigenetic drugs, especially lysine‐specific demethylase‐1 inhibitors, have shown promising activity in inhibiting CSCs and suppressing EMT. Furthermore, reprogramming of vital immune‐ and homologous recombination‐related genes through specific epigenetic modulation might synergistically enhance the antitumor activity of a PARPi/checkpoint inhibitor combination and could identify novel targetable gene signatures. FoxP3⁺ Tregs, Forkhead box P3+ regulatory T cells; MDSC, myeloid‐derived suppressor cells; PD‐1, programmed cell death‐1; TILs, tumor‐infiltrating lymphocytes