X-ray-responsive dissolving microneedles mediate STING pathway activation to potentiate cutaneous melanoma radio-immunotherapy

Background: Radiotherapy (RT) often activates the cyclic GMP-AMP synthase (cGAS) stimulator of interferon response cGAMP interactor (STING) signaling pathway and induces systemic immunotherapy effects by triggering immunogenic cell death (ICD) in various solid tumors. However, RT-induced ICD usually falls short in eradicating distant tumors because of moderate anti-tumor immune responses. Methods: In this study, Mn-ZIF-8 nanoparticles and microneedles were prepared, and their physical and chemical properties were characterized. Subsequently, in vitro experiments using B16 and A375 cutaneous melanoma cell lines were conducted to investigate the radiosensitivity characteristics of Mn-ZIF-8 and its mechanism for enhancing RT efficacy. Moreover, mouse models bearing primary and distant B16 cutaneous melanoma were established to clarify the immunomodulatory effect and antitumor efficacy of Mn-ZIF-8 microneedles when combined with RT and immunotherapy. Results: A percutaneous delivery method based on soluble microneedles (MNs) with Mn²⁺-loaded, X-ray-responsive zeolite imidazolate frame-8 (ZIF-8) was designed. This microneedle-based drug delivery system, combined with RT, promoted the radiosensitivity of cutaneous melanoma and reinforces ICD by augmenting STING pathway activation. Furthermore, after X-ray irradiation, Mn-ZIF-8 MNs continuously released Mn²⁺ in the tumor to enhance cGAS-STING activation. This promoted dendritic cell maturation and antigen presentation, and potentiated a T cell mediated immune response. Thus, the local and systemic immune effects induced by RT were amplified when combined with immune checkpoint inhibitors. Conclusion: The microneedle patches with X-ray-responsive, rapid dissolution and controlled release abilities have the potential to enhance the radioimmunotherapy efficacy for cutaneous melanoma.