PARP inhibitors and the tumor micro-environment: Bidirectional crosstalk, resistance mechanisms, and therapeutic opportunities.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized in precision oncology, particularly in tumors harboring homologous recombination deficiency (HRD), such asovarian and breast cancers. Despite their clinical success, both primary and acquired resistance substantially limit the durability and breadth of therapeutic benefit, indicating that tumor-intrinsic DNA repair defects alone are insufficient to fully explain treatment outcomes. Accumulating evidence highlights the tumor microenvironment (TME) as a critical determinant of PARPi sensitivity and resistance. This review provides a comprehensive and mechanistic overview of the bidirectional crosstalk between PARPi and the TME. We first summarize both classical and non-classical mechanisms of PARPi action, extending beyond synthetic lethality to include PARP trapping, replication stress, immune activation, and metabolic reprogramming. We then systematically dissect how key TME components-including immune cells, cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), hypoxia, and metabolic networks-modulate PARPi efficacy. Importantly, we highlight the dual nature of PARPi-mediated TME remodeling: while PARPi can activate cGAS-STING-dependent antitumor immunity, normalize tumor vasculature, and soften stromal barriers, they may simultaneously induce adaptive resistance through immune checkpoint upregulation, immunosuppressive cell recruitment, and metabolic compensation. Finally, we discuss emerging translational opportunities, emphasizing the development of TME-informed biomarkers and rational combination strategies, including immunotherapy, anti-angiogenic therapy, and metabolic interventions. A deeper understanding of TME-mediated mechanisms will be essential to optimize PARPi-based therapies and overcome resistance in the clinical setting.