Mannosylated graphene oxide nanotherapeutics co-delivering docetaxel and a STING agonist reprogram myeloid cells and potentiate antitumor immunity

In triple-negative breast Cancer (TNBC), tumor-associated macrophages (TAMs) and tumor-infiltrating dendritic cells (TIDCs) often exhibit an immunosuppressive phenotype. This myeloid-dominant milieu reinforces an immune-cold state, promotes metastasis and contributes to immunotherapy resistance. In this study, we developed a mannose-functionalized graphene oxide nanocarrier (GO-EDM) with favorable biocompatibility and high NIR photothermal conversion efficiency. Docetaxel and vadimezan (DMXAA), a prototypical STING agonist, were co-loaded into GO-EDM to generate GO-EDM-DTX-Vad. In vitro, the nanocomposite promoted M2-to-M1 repolarization, thereby attenuating pro-tumor paracrine signaling from M2 macrophages and limiting TNBC cell proliferation, migration and invasion. Concomitantly, it promoted dendritic cell maturation and induced immunogenic cell death (ICD) in tumor cells, collectively enhancing antigen presentation and T-cell activation. In vivo, both intratumoral administration and systemic intravenous administration of GO-EDM-DTX-Vad effectively suppressed primary tumor growth. In a lung metastasis model, when combined with 808 nm NIR irradiation, the pulmonary metastatic burden was significantly reduced. Specifically, this treatment reduced the accumulation of M2 macrophages, MDSCs and Tregs within tumors, while promoting DC maturation and increasing intratumoral infiltration of M1 macrophages, CD8⁺ T cells and memory T cells. Taken together, GO-EDM-DTX-Vad leverages passive tumor accumulation and mannose receptor-guided dual targeting of TAMs and TIDCs to integrate DTX-based chemotherapy, STING-mediated immune activation and mild NIR photothermal therapy. This integrated chemo-photothermal-immunotherapeutic design couples direct tumor cell killing with myeloid reprogramming and immune activation, offering a unified strategy for metastatic TNBC.

Graphene oxide; Immunogenic cell death; Lung metastasis; STING agonist; Triple negative breast cancer; Tumor-associated macrophage repolarization.