PARylation-centric crosstalk: orchestrating immune evasion and multidrug resistance in ovarian cancer

Post-translational modifications (PTMs) play pivotal roles in ovarian cancer pathogenesis, with poly(ADP-ribosyl)ation (PARylation) serving as a key regulator of DNA repair, immune evasion, and therapeutic resistance. Beyond PARylation, diverse PTM networks-including ubiquitination, phosphorylation, acetylation, methylation, and glycosylation-orchestrate signaling cascades that shape tumor progression and immune recognition. Aberrant glycosylation of MUC16 (CA125) and immune checkpoints such as PD-L1 exemplifies how PTMs modulate the tumor immune microenvironment. This review synthesizes current evidence on the interplay between PARylation and other PTM networks in ovarian cancer, with emphasis on their roles in DNA repair, immune modulation, and drug resistance. We discuss PARP1/2-mediated regulation of cGAS/STING signaling and immune cell activity, alongside resistance mechanisms involving EHMT1/2-associated histone methylation, SPINDOC-enhanced PARylation, and ubiquitin-dependent PARP1 stabilization. Therapeutically, we evaluate combinatorial approaches pairing PARP inhibitors with ATR/CHK1 inhibition, immune checkpoint blockade, or metabolic targeting. Emerging strategies combining PARP inhibitors with PRMT, UBA1, WEE1, or MEK inhibitors are examined, alongside recent clinical trials including the GINECO study of bevacizumab, olaparib, and durvalumab. Mechanistic insights into PARP inhibitor-induced T cell DNA damage and strategies to preserve lymphocyte function are also discussed. Preclinical approaches involving nanoparticle delivery, PROTACs, and ferroptosis induction are reviewed for their potential to disrupt PARylation networks. Despite these advances, clinical translation faces substantial challenges, including patient heterogeneity, overlapping toxicities, adaptive resistance through PTM network rewiring, and the need for predictive biomarkers beyond BRCA mutation status. Current obstacles in resolving spatiotemporal PTM dynamics and cancer stem cell-specific vulnerabilities are outlined. This work aims to inform future research on targeting PARylation-associated PTM pathways to overcome ovarian cancer's evolvable resistance.