An organolutetium nanosensitizer synergizes with PARP inhibition to unleash STING-mediated immunity for low-dose radioimmunotherapy

<b>Rationale:</b> The efficacy of radiotherapy in triple-negative breast cancer (TNBC) is often limited by an immunosuppressive tumor microenvironment (TME), requiring high radiation doses that cause systemic toxicity. There is a critical need for theranostic strategies capable of guiding therapy and amplifying the efficacy of low-dose radiation. <b>Methods:</b> We developed a multifunctional organolutetium nanosensitizer (LSPA) for image-guided, low-dose radioimmunotherapy. Lutetium (Lu) serves as both a contrast agent for CT imaging and a radiosensitizer through the generation of reactive oxygen species (ROS). The LSPA nanoparticles were engineered to selectively accumulate in tumors and release their therapeutic payload in response to the acidic TME. <b>Results:</b> At a low 6 Gy X-ray dose, LSPA synergized with the PARP inhibitor Olaparib to induce extensive DNA damage. This activated the cGAS-STING pathway and remodeled the TME. The treatment promoted immunogenic cell death, dendritic cell maturation, and M1 macrophage repolarization. It also decreased regulatory T cells, leading to increased CD4⁺ and CD8⁺ T cell infiltration in both primary and metastatic tumors. <b>Conclusion:</b> This theranostic strategy suppressed primary and distant (abscopal) tumors, prevented recurrence, and established durable immune memory with low-dose irradiation. Our findings present a clinically translatable approach that combines a nanosensitizer with PARP inhibition to turn immunologically "cold" tumors into "hot" ones, thereby enhancing the efficacy of low-dose radioimmunotherapy while limiting systemic toxicity.