Radionuclide-stimulated dynamic therapy induces complementary immunogenic necroptosis and apoptosis cancer cell death pathways.

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth or lung metastasis. However, in immunocompetent models, RaST induced a partial and complete response (CR) with no metastasis, driven by the recruitment of CD11b+, CD11c+, and CD8b+ effector immune cells. A cancer-imaging agent, LS301, identified latent minimal residual disseminated tumors in the lymph nodes of the CR group. Although cancer cells in CR mice enhanced protumor cytokines and immune checkpoints over time, RaST maintained cancer control through dynamic redistribution of ROS-regenerative titanium dioxide nanoparticles from bones to spleen and lymph nodes, supporting sustained immunity. This study highlights how RaST reprograms tumor immunity, overcoming apoptosis resistance by activating complementary necroptosis.