Catalytically Active Metal-Organic Frameworks Elicit Robust Immune Response to Combination Chemodynamic and Checkpoint Blockade Immunotherapy

Chemodynamic therapy (CDT) strategies rely on the generation of reactive oxygen species (ROS) to kill tumor cells, with hydroxyl radicals (center dot OH) serving as the key mediators of cytotoxicity in this setting. However, the efficacy of CDT approaches is often hampered by the properties of the tumor microenvironment (TME) and associated limitations to the Fenton reaction that constrains ROS generation. As such, there is a pressing need for the design of new nanoplatforms capable of improving CDT outcomes. In this study, an Fc-based metal-organic Co-Fc) was developed. This platform was capable of undergoing TME-responsive degradation without impacting normal cells. After its release, Vk3 was processed by oxidoreductase-1 (NQO1), which is highly expressed in tumor cells, thereby yielding large quantities of H2O2 that in turn interact with Fe ions via the Fenton reaction to facilitate in situ cytotoxic center dot OH production. This process leads to immunogenic cell death (ICD) of the tumor, which then promotes dendritic cell maturation and ultimately increases T cell infiltration into the tumor site. When this nanoplatform was combined with programmed death 1 (PD-1) checkpoint blockade approaches, it was sufficient to enhance tumor-associated immune responses in breast cancer as evidenced by increases in the frequencies of CD45(+) leukocytes and CD8(+) cytotoxic T lymphocytes, thereby inhibiting tumor metastasis to the lungs and improving murine survival outcomes. Together, this Vk3@Co-Fc cascading catalytic nanoplatform enables potent cancer immunotherapy for breast cancer regression and metastasis prevention.

Automated summary

In this study, a Fc-based metal-organic Co-Fc nanoplatform was developed for targeted therapy of tumor cells. The platform released a large amount of H2O2 through a TME-responsive degradation process and interacted with Fe ions via the Fenton reaction to produce cytotoxic •OH. This nanoplatform, when combined with PD-1 checkpoint blockade, enhanced immune responses and prevented metastasis in breast cancer.