Purpose <p>The aim of this study is to overcome the challenges of poor tumor penetration and systemic toxicity in targeted alpha therapy (TAT) while also evaluating its immunomodulatory effects to enhance antitumor immune responses in melanoma treatment.</p> Methods <p>This study developed a ²¹¹At-labeled single-domain antibody agent ([²¹¹At]At-AuNP-ABDMPL16) targeting PD-L1, a protein overexpressed in melanoma cells. The binding affinity and internalization of [²¹¹At]At-AuNP-ABDMPL16 were evaluated in vitro using melanoma cell lines. In vivo studies in melanoma-bearing mice were conducted to assess biodistribution, pharmacokinetics, therapeutic efficacy, and the immune response induced by the treatment.</p> Results <p>[²¹¹At]At-AuNP-ABDMPL16 demonstrated high binding affinity and efficient internalization in melanoma cells, resulting in significant tumor cell death through α-particle radiation. In vivo, [²¹¹At]At-AuNP-ABDMPL16 preferentially accumulated in tumors, inhibited tumor growth, and prolonged survival in melanoma-bearing mice. The treatment also triggered a robust anti-tumor immune response, marked by increased cytotoxic T lymphocytes and reduced regulatory T cells within the tumor microenvironment, with minimal systemic toxicity.</p> Conclusion <p>[²¹¹At]At-AuNP-ABDMPL16 shows promise as a novel therapeutic for melanoma, combining effective tumor targeting with potent cytotoxic and immune-activating effects. These findings support further investigation of this ²¹¹At-labeled single-domain antibodies in clinical applications.</p>