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

Arsenic trioxide (As2O3) 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 MnZnSX nanorods (As-MnZnSX NRs) to enhance both the efficacy and safety of As2O3 in hepatocellular carcinoma treatment. These nanorods are engineered to release Mn2+ and H2S 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, AsIII. The results demonstrate that Mn2+ amplifies the cGAS-STING pathway by inducing TBK1 phosphorylation and IRF3 activation, leading to dendritic cell maturation and improved tumor antigen cross-presentation. Simultaneously, H2S promotes prodrug conversion and enhances immune activation, collectively driving binary stimulation of the cGAS-STING pathway. This strategy significantly augments the antitumor efficacy of As2O3 by integrating immune modulation with targeted cytotoxic effects. Furthermore, MnZnSX 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.