The development of immunotherapy, in particular immune checkpoint inhibitors (ICI), has revolutionized cancer treatment in the past decades. However, its efficacy is still limited to subgroups of patients with cancer. Therefore, effective treatment combination strategies are needed. Here, radiotherapy is highly promising, as it can induce immunogenic cell death, triggering the release of pro-inflammatory cytokines, thereby creating an immunogenic phenotype and sensitizing tumors to ICI. Recently, targeted radionuclide therapy (TRT) has attained significant interest for cancer treatment. In this approach, a tumor-targeting radiopharmaceutical is used to specifically deliver a therapeutic radiation dose to all tumor cells, including distant metastatic lesions, while limiting radiation exposure to healthy tissue. However, fundamental differences between TRT and conventional radiotherapy make it impossible to directly extrapolate the biological effects from conventional radiotherapy to TRT. In this review, we present a comprehensive overview of studies investigating the immunomodulatory effects of TRT and the efficacy of combined TRT-ICI treatment. Preclinical studies have evaluated a variety of murine cancer models in which α- or β-emitting radionuclides were directed to a diverse set of targets. In addition, clinical trials are ongoing to assess safety and efficacy of combined TRT-ICI in patients with cancer. Taken together, research indicates that combining TRT and ICI might improve therapeutic response in patients with cancer. Future research has to disclose what the optimal conditions are in terms of dose and treatment schedule to maximize the efficacy of this combined approach.

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