Nanoscale Metal-Organic Frameworks for Cancer Immunotherapy

Immunotherapy has revolutionized cancer treatment by reactivating host anti-tumor immunity with durable efficacy and limited toxicity. However, only a small portion of patients with immunostimulatory tumor microenvironments respond to cancer immunotherapy. Various methods have been explored to turn “cold” tumors “hot”. Chapter 1 broadly discusses current immunoadjuvant therapies to synergize with cancer immunotherapy, particularly checkpoint blockade immunotherapy, and a brief overview of nanoscale metal-organic frameworks (nMOFs), a new class of porous molecular nanomaterials with potential for biomedical applications. The introduction to the fundamental principle of design and application of nMOFs to generate reactive oxygen species (ROS) for cancer treatment, including radiotherapy (RT), photodynamic therapy (PDT), and chemodynamic therapy (CDT), serve as a foundation for Chapters 2-6. Chapter 2 discusses the rational design of two Hf-oxo based nMOFs, Hf6-DBA and Hf12-DBA, as highly effective radiosensitizers that significantly outperform HfO2, a clinically investigated radiosensitizer. The radiosensitization of Hf-based nMOFs are attributed to large specific surface areas, facile ROS diffusion and enhanced energy deposition. Intratumorally injected nMOFs induce immunogenic cell death upon low-dose X-ray irradiation for local inflammation. Importantly, the combination of nMOF-mediated low-dose RT with an anti-programmed death-ligand 1 antibody effectively extends the local therapeutic effects of RT to distant tumors via abscopal effects. Chapter 3 describes the design of Hf-DBB-Ru as a mitochondria-targeted nMOF for RT-RDT to further enhance local radiosensitization. Constructed from Ru-based photosensitizers, the cationic framework exhibits strong mitochondria-targeting property. Upon X-ray irradiation, Hf-DBB-Ru efficiently generates hydroxyl radicals from the Hf6 SBUs and singlet oxygen from the DBB-Ru photosensitizers in a unique RT-RDT mode of action. Mitochondria-targeted RT-RDT depolarizes the mitochondrial membrane to initiate apoptosis of cancer cells, leading to significant tumor regression in mouse models and outperforming Hf6-DBA reported in Chapter 2. Chapter 4 reports the design of an ultrathin version of nMOFs, Hf-MOL, with reduced dimensionality to facilitate the diffusion of ROS generated by RT-RDT to promote anti-tumor efficacy. Hf-MOL not only outperforms Hf12-DBA reported in Chapter 2 for local RT-RDT, while eradicates local tumors and rejects distant tumors on several syngeneic bilateral tumor models in conjunction with various checkpoint blockade inhibitors, and eliminates lung metastases by reactivating anti-tumor immunity and inhibiting myeloid-derived suppressor cells. Chapter 5 describes the design of cationic nMOF, Hf-DBBF-Ir, to release danger associated molecular patterns (DAMPs) and tumor antigens (TAs) via RT-RDT and deliver pathogen-associated molecular patterns (PAMPs), anionic CpG oligodeoxynucleotides, to facilitate the maturation of antigen presentation cells (APC). Together, DAMPs, TAs, and PAMPs promote APC maturation and activate cytotoxic T cells to reinvigorate adaptive immune system. Chapter 6 illustrates the use of a Cu-porphyrin nMOF, Cu-TBP, to mediate synergistic hormone-triggered chemodynamic therapy (CDT) and light-triggered photodynamic therapy (PDT) as radical therapy to boost local inflammation. By hijacking dysregulated hormone production, Cu2+ catalytically consumes estradiol for ROS generation. The combination of CDT- and PDT-based radical therapies shows effective anti-tumor efficacies in hormonally dysregulated tumor phenotypes. Combination of nMOF-mediated radical therapy with CBI elicits extends the local therapeutic effects of CDT and PDT to distant tumors with systemic antitumor immunity