Cancer-cell-mimicking MnO2 nanoplatform delivers immunological adjuvants to enhance radio-immunotherapy

Abstract

The hypoxic and immunosuppressive microenvironment within tumors represents a fundamental mechanism contributing to radiotherapy (RT) resistance, which is closely linked to poor prognosis in cancer patients. To overcome these limitations, we constructed a tumor cell membrane-mimetic manganese-based nanoplatform for delivering immune adjuvants (MnO2-R848@CM) to synergistically enhance the efficacy of clinical radiotherapy. In vitro experiments demonstrated that MnO2-R848@CM is rapidly and specifically taken up by 4T1 cells. Upon X-ray irradiation, immunogenic cell death (ICD) and released Mn2+ activated the cGAS-STING pathway in dendritic cells (DCs), synergistically accelerating DCs maturation alongside R848 to trigger downstream immune response cascades. In breast cancer mouse models, MnO2–R848@CM exhibited highly effective homotargeting properties, rapidly accumulating and persisting at tumor sites. It further established a long-lasting adaptive anti-tumor immune response via multiple pathways, effectively accelerating tumor ablation and significantly inhibiting tumor growth in tumor-bearing mice. These findings highlight the potential of the MnO2–R848@CM nanoplatform in advancing synergistic cancer radioimmunotherapy, which effectively integrates the direct cytotoxic effects of radiotherapy with ongoing antitumor immune responses.