Enhancing Triple-Negative Breast Cancer Radiotherapy via EZH2-Targeted Nanoplatform and Radionuclide Therapy

Triple-negative breast cancer (TNBC) presents considerable treatment difficulties because of its highly aggressive behavior and the absence of targeted therapeutic options. This study aimed to develop a tumor microenvironment-responsive nanoplatform combining the enhancer of zeste homologue 2 (EZH2) inhibition and targeted radionuclide therapy (TRT) to enhance antitumor efficacy and remodel immunosuppressive signaling in TNBC. A cancer cell membrane (CCm)-camouflaged nanoplatform (CCm-HSA-Taz) was engineered to encapsulate the EZH2 inhibitor Tazemetostat (Taz), enabling tumor-targeted delivery. The nanoplatform was coadministered with [¹⁷⁷Lu]Lu-based TRT to evaluate synergistic effects. Physicochemical characterization assessed the nanoplatform stability. In vivo efficacy was tested in TNBC-bearing murine models with tumor progression monitored via imaging and histopathology. The CCm-HSA-Taz nanoplatform exhibited favorable physicochemical properties and excellent stability. In vivo radioimmunoassay studies indicated that the immune response in the CCm-HSA-Taz combined with the [¹⁷⁷Lu]Lu radiotherapy was stronger than that observed in the CCm alone or in the [¹⁷⁷Lu]Lu radiotherapy alone. Additionally, the combination group exhibited an observed increase in the apoptotic cell population, and antitumor immunity was enhanced at the conclusion of the 19-day observation period. Furthermore, all results were corroborated through pathological and imaging examinations. We developed a tumor microenvironment-adaptive nanoplatform delivering Taz to disrupt immunosuppression and enhance radiotherapy sensitivity in TNBC, without significant side effects in animal models. Nuclear medicine imaging revealed reduced tumor glucose metabolism and improved immune cell cytotoxicity. Utilizing components approved by the FDA suggests the potential for this strategy to be translated into clinical settings.