Ultrasound-triggered dissolving microneedle platform for cGAS-STING-mediated precision immunotherapy of melanoma

Melanoma is an aggressive skin cancer with a rapidly increasing global incidence. Immunotherapy via the cGAS-STING pathway has emerged as a promising strategy to enhance anti-tumor efficacy in melanoma, however, its clinical translation remains limited by several challenges. Herein, we reported an ultrasound (US)-controllable all-in-one dissolving microneedle (dMN) platform that integrated a ROS-cleavable prodrug, formed by conjugating the VEGF inhibitor linifanib, with ROS-responsive liposomes encapsulating the sonosensitizer MnTCPP (Mn@CTL-LPs dMNs). This system simultaneously inhibited tumor cell proliferation through ROS and linifanib while activating the cGAS-STING pathway to promote immunotherapy. Upon skin insertion, Mn@CTL-LPs dMNs dissolved in the interstitial fluid, releasing Mn@CTL-LPs. Without US exposure, the system remained biologically inert and exhibited minimal cytotoxicity, whereas US irradiation triggered ROS generation, promoted linifanib release, and induced DNA damage, collectively inducing the death of tumor cells. Meanwhile, MnTCPP released into the tumor microenvironment underwent reduction from Mn³⁺ to Mn²⁺ in the glutathione (GSH)-rich milieu, which enhanced cGAS-STING activity. Importantly, the synergistic DNA damage and Mn²⁺-mediated pathway activation robustly promoted dendritic cell (DC) maturation and enhanced CD8⁺ T-cell infiltration. This spatiotemporally controllable activation ensured high therapeutic precision and safety. Overall, this work presented a noninvasive and US-triggered strategy to potentiate sonodynamic immunotherapy for melanoma.