PARP Inhibitor-Sensitized Radionuclide Therapy Combined With Immune Checkpoint Inhibitors: A Review of Mechanistic Synergy, Tumor Microenvironment Remodeling, and Systemic Immune Effects

Radionuclide therapy has garnered significant attention for its ability to be precisely delivered to tumor sites, particularly in metastatic cancers not effectively controlled by conventional external beam radiation. However, the efficacy of radionuclide therapy alone is often suboptimal, making the exploration of radionuclide-based combination regimens critically important. The “triple therapy” strategy of PARP inhibitor (PARPi)-sensitized radionuclide therapy (RNT) combined with immune checkpoint inhibitors (ICI) aims to overcome the limitations of monotherapies through multi-mechanistic synergy, thereby enhancing antitumor efficacy. This review summarizes the synergistic mechanisms underlying this combination strategy, focusing on the DNA damage and replication stress induced by the synergy between PARPi and RNT, as well as the consequent remodeling of the tumor microenvironment (TME), including the induction of immunogenic cell death (ICD), alterations in immune cell infiltration, and the weakening of immunosuppressive barriers. These local effects ultimately synergize with ICI, potentially activating a robust systemic antitumor immune response. We systematically summarize the preclinical evidence for this strategy, review the progress of ongoing clinical trials, and discuss its challenges and future directions, aiming to provide a theoretical basis for optimizing combination cancer therapies.