Radiolabeled Coordination Polymer-Loaded Microneedles for Synergistic Melanoma Brachytherapy-Immunotherapy via STING Activation and Pyroptosis.

Melanoma remains a highly aggressive malignancy with limited response to current immunotherapies due to its immunosuppressive tumor microenvironment. To overcome this limitation, we developed a radiolabeled coordination polymer, 177Lu-GAMP, through the self-assembly of 177Lu3+ with adenosine monophosphate (AMP) and guanosine monophosphate, exhibiting coordination-feature resemblance to the endogenous STING agonist cGAMP, thereby enabling activation of the STING pathway. We further incorporated 177Lu-GAMP into a dissolvable microneedle patch (177Lu-GAMP@MN) for localized, minimally invasive delivery to melanoma lesions. Our results demonstrate that 177Lu-GAMP@MN effectively penetrated the skin and retained at the tumor site, leading to robust STING activation and Gasdermin E-mediated pyroptosis. This, in turn, promoted dendritic cell maturation and enhanced T cell infiltration. In vivo, 177Lu-GAMP@MN significantly suppressed subcutaneous melanoma growth, prolonged survival, and elicited strong antitumor immune responses. When combined with anti-PD-L1 monoclonal antibodies, the treatment achieved synergistic tumor regression, improved effector T cell function, and induced durable immunological memory, demonstrating significant inhibition of both primary and distant tumors in murine models. Collectively, this work presents a transdermal brachytherapeutic-immunomodulatory strategy for melanoma treatment, offering promising potential for enhanced antitumor immunotherapy.