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Rationale: Androgen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized disease. However, for metastatic castration-resistant prostate cancer, EBRT is typically only used in the palliative setting, because of the inability to radiate all sites of disease. Systemic radiation treatments that preferentially irradiate cancer cells, known as radiopharmaceutical therapy or targeted radionuclide therapy (TRT), have demonstrable benefits for treating metastatic prostate cancer. Here, we explored the use of a novel TRT, 90 Y-NM600, specifically in combination with ADT, in murine prostate tumor models., Methods: 6-week-old male FVB mice were implanted subcutaneously with Myc-CaP tumor cells and given a single intravenous injection of 90 Y-NM600, in combination with ADT (degarelix). The combination and sequence of administration were evaluated for effect on tumor growth and infiltrating immune populations were analyzed by flow cytometry. Sera were assessed to determine treatment effects on cytokine profiles., Results: ADT delivered prior to TRT (ADT→TRT) resulted in significantly greater antitumor response and overall survival than if delivered after TRT (TRT→ADT). Studies conducted in immunodeficient NRG mice failed to show a difference in treatment sequence, suggesting an immunological mechanism. Myeloid-derived suppressor cells (MDSCs) significantly accumulated in tumors following TRT→ADT treatment and retained immune suppressive function. However, CD4+ and CD8+ T cells with an activated and memory phenotype were more prevalent in the ADT→TRT group. Depletion of Gr1+MDSCs led to greater antitumor response following either treatment sequence. Chemotaxis assays suggested that tumor cells secreted chemokines that recruited MDSCs, notably CXCL1 and CXCL2. The use of a selective CXCR2 antagonist, reparixin, further improved antitumor responses and overall survival when used in tumor-bearing mice treated with TRT→ADT., Conclusion: The combination of ADT and TRT improved antitumor responses in murine models of prostate cancer, however, this was dependent on the order of administration. This was found to be associated with one treatment sequence leading to an increase in infiltrating MDSCs. Combining treatment with a CXCR2 antagonist improved the antitumor effect of this combination, suggesting a possible approach for treating advanced human prostate cancer., Competing Interests: Competing interests: JPW is a co-founder and Senior Science Advisor for Archeus Technologies, which holds the license rights to NM600-related technologies. ZSM and RH have financial interest in Archeus Technologies. HCR has served as a consultant for Archeus Technologies. ZSM is a member of the Scientific Advisory Boards for Archeus Technologies, Seneca Therapeutics, and NorthStar Medical Isotopes. ZSM is an inventor on patents or filed patents managed by the Wisconsin Alumni Research Foundation relating to immunotherapies and the interaction of targeted radionuclide therapies and immunotherapies. The other authors have no relevant potential conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)