Tanshinone IIA&Icaritin -MPs regulated vascular normalization and restored tumor-infiltrating T lymphocyte function to boost anti-PD-1 therapy in melanoma lung metastasis

BACKGROUND: PD-1 inhibitors are a promising treatment for melanoma, but over 50% of patients with metastatic melanoma do not respond well. This limited efficacy is partly due to the aberrant vascular structure and immunosuppressive microenvironment in metastatic lung tissue. METHODS: We developed an extracellular vesicle-based delivery system Tanshinone IIA & Icaritin -MPs (TSA&ICT-MPs) that targets lung metastases. In vivo in vitro models, cell experiments, immunofluorescence, immunohistochemistry, flow cytometry, and mass spectrometry flow cytometry were used to validate the efficacy of TSA&ICT-MPs in promoting vascular normalization, enhancing the activity of tumor-infiltrating lymphocytes (TILs), and reducing myeloid-derived inhibitory cell (MDSC) infiltration by modulating the adenosine metabolic pathway. RESULTS: TSA&ICT-MP contributes to vascular normalization by modulating ELTD1, thereby enhancing TIL infiltration, and reduces adenosine release by targeting ENPP1, thus enhancing anti-tumor immunity. Combining TSA&ICT-MP with α-PD-1 achieved a 70.33% suppression rate of lung metastasis and prolonged survival in murine models. This approach offers a promising strategy to enhance the efficacy of melanoma immunotherapy.