Specific activation of cGAS-STING pathway by manganese-doped bioactive glasses for boosting systemic tumor immunotherapy

Abstract

The recurrence and metastasis of renal cell carcinoma present significant challenges in clinical settings, necessitating the urgent development of strategies to enhance the efficacy of kidney cancer treatments. In this study, we designed and developed a manganese-doped bioactive glass-based (Mn-MBG) core, creating a Mn-rich nanotherapeutic platform named MMPI. This platform was further modified by encapsulation with polydopamine (PDA) and successfully loaded with the photosensitizer indocyanine green (ICG) through π-π stacking interactions, enabling photothermal therapy (PTT) and photodynamic therapy (PDT). In vitro experiments demonstrated that under near-infrared (NIR) irradiation, MMPI could generate a moderate photothermal effect, causing damage to tumor cells. At the same time, the photothermal effect enhanced Mn²⁺ and ICG release and increased reactive oxygen species (ROS) production, intensifying damage to heat-sensitive tumor cells and aiding tumor elimination. In vivo experiments showed that MMPI can counteract the tumor’s immunosuppressive environment by activating the cGAS-STING pathway, boosting local innate immune cell recruitment, dendritic cell maturation, and T cell-mediated adaptive antitumor responses. In conclusion, this study elucidates the concept of a manganese-based non-invasive tumor immunotherapy model, establishing a paradigm for immunotherapeutic approaches in renal cell carcinoma.