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 (¹O₂) 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 ¹O₂. TCPP(Fe) ligand catalyzes the degradation of H₂O₂ to generate O₂ 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.