A Metal–Organic Framework-Based Immune-Regulating Nanocarrier Depot for Enhanced Combination Cancer Immunotherapy

Immunotherapy is a promising cancer treatment with great clinical success. However, its low response rate for many types of cancers is still a limitation owing to the tumor immunosuppressive microenvironment. Herein, an iron-based nanoscale metal-organic framework (MOF) is constructed as a drug carrier with immune-stimulating activity. After reduction and maleimide grafting of basic NH₂-MIL-88B, the synthesized MOF (rMOF-MA) dramatically increases the production of reactive oxygen species. Accompanied with a high amount of intracellular iron accumulation originating from endocytosis by macrophages, rMOF-MA thus promotes the polarization of macrophages from anti-inflammatory M2 to pro-inflammatory M1 for reprogramming the tumor microenvironment and enhancing immune response. After loading with immune adjuvant resiquimod (R848) and further encapsulation by a tissue-adhesive hydrogel, a local inflammatory niche is constructed. When further combined with immune checkpoint blockade (ICB) therapy, the hydrogel-based combination immunotherapy exhibits strengthened systemic antitumor immunity and significantly inhibits tumor growth, lung metastasis, and tumor recurrence after surgery. Therefore, this MOF-based immune-regulating depot exhibits potential as a promising agent for clinical cancer immunotherapy.