Panel A: MRI (T1 with gadolinium contrast) was used to verify presence of melanoma brain metastasis (arrow). ⁸⁶Y-NM600 was then injected and imaged longitudinally using PET/CT imaging, and at 49 h after injection, demonstrated selective uptake into both brain metastasis and flank melanoma tumors (%ID/g = percentage injected dose per gram; arrow indicates tumor; secondary signal in flank is likely hepatobiliary/fecal). Panel B: ⁸⁶Y-NM600 uptake and retention up to 72 h demonstrated increased drug uptake in melanoma brain metastasis and flank tumors compared to normal brain (mean ± SE, n = 4 in a single animal experiment). Panel C: Ex vivo gamma counts of tissue at 72 h showed similar tumor/normal ratios comparing melanoma brain metastasis to flank tumors (mean ± SE, n = 4 in a single animal experiment). Panel D: Monte Carlo dosimetry calculations were performed to determine the dose of radiation (Gy/MBq) delivered to melanoma brain metastasis and flank tumor, and normal brain (mean ± SE, with each dot representing an individual mouse, *P < 0.05, ANOVA with post hoc Bonferroni, n = 4 in a single animal experiment). Panel E: Quantified immunohistochemistry for T-cell markers after administration of targeted radionuclide therapy (TRT) ⁹⁰Y-NM600 with and without ISV + anti-CTLA-4 regimen, with samples taken at euthanasia for survival end point and compared to untreated controls [**P < 0.01, *P < 0.05, mean ± SE with marker representing each individual mouse (i.e., average of 3 high-powered fields), ANOVA with post hoc Bonferroni, n = 4 in a single animal experiment]. Panel F: Heatmap of cytokines/chemokines analyzed via multiplex immunoassay for melanoma brain metastases in mice treated with TRT ⁹⁰Y-NM600 with and without ISV + anti-CTLA-4 regimen (z-scores; n = 5 mice in a single animal experiment). Concentrations of cytokines/chemokines in mice treated with TRT ⁹⁰Y-NM600 or WBRT with ISV + anti-CTLA-4 regimen, plotted relative to ISV + anti-CTLA-4 regimen alone (**P < 0.01, *P < 0.05, mean ± SE, ANOVA with post hoc Bonferroni, n = 5 in a single animal experiment).