Abstract: Targeted radionuclide therapy (TRT) provides an immunogenic microenvironment for immune checkpoint inhibitor (ICI) therapy by inducing DNA double-strand break, activating the cGAS-STING, NF-κB/IRF3 and STAT1/3-IRF1 pathways, up-regulating the expression of PD-L1, and increasing the infiltration of pro-inflammatory cytokines, CD8⁺ T cells and CD4⁺ T cells in tumors. The combined therapy could increase the infiltration of memory effector T cells, M1 macrophages and dendritic cells which positively regulate immune response, and downregulate immunosuppressive regulatory T cells, M2 macrophages and myeloid-derived suppressor cells. Partial complete remission and immune memory were achieved in tumor-bearing mice treated with combined therapy. It is worth noting that radiodiagnostic agent 2-¹⁸FFDG combined with anti-PD-L1 mAb could also reprogram the immune microenvironment and significantly improve therapeutic effect. This review presents typical combination therapy strategies, emphasizes the time window of combination therapy and different combinations of therapy that may improve the therapeutic effect, and proposes that radiodiagnostic agents combined with tumor immunotherapy are expected to become a new paradigm and a direction for further research in the future.