Hybrid-Ligand Metal-Organic Frameworks Enabling Radio-Radiodynamic-Chemodynamic Therapy Primes Checkpoint Blockade Immunotherapy in Hypoxic Tumors.

Radiodynamic therapy (RDT) offers a potential strategy to enhance radiation therapy (RT) efficacy by efficiently generating singlet oxygen (O) upon radiation. However, both RT and RDT can be compromised by tumor hypoxia. To relieve hypoxia while potentiating RT-RDT, we developed a hybrid-ligand nanoscale metal-organic framework (nMOF), LuMix, for radio-radiodynamic-chemodynamic therapy (RT-RDT-CDT) of tumors with low-dose X-ray. In LuMix, Lu effectively absorbs X-rays to generate hydroxyl radical (OH) and transfers energy to TCPP to produce O. TCPP(Fe) ligand catalyzes the degradation of HO to generate O and OH, alleviating hypoxia and enabling CDT. We further combined RT-RDT-CDT with checkpoint blockade immunotherapy to demonstrate the effective control of primary and distant tumor progression. In a bilateral colorectal cancer mouse model, LuMix combined with anti-PD-1 (αPD-1) effectively induced an abscopal effect under low-dose X-ray treatment (2 Gy for 3 days consecutively) with 97.3% primary tumor inhibition and 98.5% distant tumor inhibition. Notably, one of six primary tumors and two of six distant tumors were eradicated after treatment. Immunological analysis demonstrates that LuMix-enabled RT-RDT-CDT effectively promotes cytokine release and thereby enhances DC recruitment in the tumor-draining lymph nodes. Meanwhile, αPD-1 facilitates DC maturation and tumor-associated antigens presentation and increases CD8 T cell infiltration in both the primary and distant tumors. The RT-RDT-CDT-induced damage also recruits macrophages to tumor sites and downregulates Tregs to activate the immune microenvironment. We therefore demonstrate a feasible strategy to fabricate radiosensitizers to synergize RT-RDT-CDT with checkpoint blockade immunotherapy.