Combined radioligand therapy and immunotherapy for cancer: research advances and translational challenges

Radioligand therapy (RLT) delivers therapeutic radionuclides to tumor-associated targets through specific targeting ligands and has demonstrated substantial clinical value in malignancies such as prostate cancer and neuroendocrine tumors. Beyond its direct induction of radiation-mediated tumor cell damage, RLT has attracted increasing attention for its potential immunomodulatory effects. Current evidence suggests that RLT may create local immune conditions favorable for immunotherapy by promoting tumor antigen release, enhancing antigen presentation, and modulating the tumor immune microenvironment. Immunotherapy, particularly immune checkpoint inhibitors, can restore or enhance T cell-mediated antitumor immune responses. Accordingly, RLT and immunotherapy are mechanistically complementary and have shown synergistic antitumor activity in several preclinical models. However, clinical evidence supporting this combination remains preliminary, and whether preclinical synergy can be consistently translated into meaningful clinical benefit is still unclear. Following a “mechanism–evidence–translation” framework, this review summarizes the radioimmunological rationale, preclinical evidence, and clinical progress of RLT combined with immunotherapy. It also provides a descriptive overview of the available evidence and discusses key translational challenges, including dosimetry, treatment sequencing, patient selection, and long-term safety, with the aim of informing the optimization of future combination strategies and clinical trial design.