Bimetallic MnZnS Nanotheranostics for Self-Activatable Chemo-Immunotherapy of Hepatocellular Carcinoma via H₂S-Triggered Arsenic Prodrug Activation and Binary cGAS-STING Pathway Modulation.

Arsenic trioxide (AsO) has long been utilized in traditional Chinese medicine due to its therapeutic properties. While it exhibits potent anticancer activity, its clinical application is hindered by systemic toxicity and limited tissue specificity. In this study, an advanced therapeutic approach is developed using arsenic prodrug-loaded bimetallic sulfide MnZnS nanorods (As-MnZnS NRs) to enhance both the efficacy and safety of AsO in hepatocellular carcinoma treatment. These nanorods are engineered to release Mn and HS within the tumor microenvironment, facilitating binary-cooperative activation of the cGAS-STING pathway. This dual activation mechanism enhances immune responses while converting the arsenic prodrug into its cytotoxic form, As. The results demonstrate that Mn amplifies the cGAS-STING pathway by inducing TBK1 phosphorylation and IRF3 activation, leading to dendritic cell maturation and improved tumor antigen cross-presentation. Simultaneously, HS promotes prodrug conversion and enhances immune activation, collectively driving binary stimulation of the cGAS-STING pathway. This strategy significantly augments the antitumor efficacy of AsO by integrating immune modulation with targeted cytotoxic effects. Furthermore, MnZnS nanorods enable in vivo MRI, allowing real-time monitoring of treatment progression. This study represents a substantial advancement in liver cancer therapy by integrating chemoimmunotherapy with diagnostic imaging, thereby improving therapeutic precision while minimizing systemic toxicity.