Radiosensitizing in situ cancer vaccines combined with immune checkpoint blockade to overcome resistance to radioimmunotherapy.

Radiotherapy is a widely used cancer treatment; however, it is often limited by adverse effects on normal tissues, treatment-resistant tumor microenvironment (TME), and low efficacy in distant tumors. To address these limitations, TME-regulating Fe3O4 radiosensitizer was coated with immunogenic mesoporous silica (MS) to create Fe3O4@MS-NH2, which serves as both radiosensitizer and immune sensitizing adjuvant. Tumor cells cultured with Fe3O4 nanoparticles exhibited up to 2.8-fold increased DNA damage and 1.6-fold higher levels of ROS, alongside an oxygen probe concentration as low as 55 % and a GSH/GSSG ratio as low as 47 %, compared to those cultured without Fe3O4 nanoparticles. When comparing the tumor volumes of untreated mice to those treated with a combination of Fe3O4@MS-NH2-TLR7a, immune checkpoint inhibitors, and radiotherapy, the volumes of treated MOC2 tumors were reduced to as low as 10.9 %, while distant untreated MOC2 tumors measured only 45.9 %. Mice undergoing this combination treatment modulated TME, including a MDSC percentage as low as 73.2 %, a M2 macrophage percentage as low as 55.8 %, a 3.5-fold increase in M1 macrophages, and a 2.9-fold increase in memory T cells, a 2.7-fold increase in central memory T cells, a 2.2-fold increase in IFN-γ+ T cells, and a 3.7-fold increase in TNF-α+ T cells. The combination of Fe3O4@MS-NH2-TLR7a, immune checkpoint inhibitors, and radiotherapy is expected to boost radiotherapy.