Synergistic STING Activation and Oxidative Cascades-Induced Ferroptosis Drive Tumor Microenvironment Remodeling by Engineered Manganese Nanoreactors

In head and neck squamous cell carcinoma, a "cold" (immune-desert) tumor microenvironment promotes immunosuppression, which is a critical driver of disease recurrence and therapeutic resistance. To address this challenge, we develop an innovative strategy to remodel the tumor immune microenvironment by disrupting intracellular redox balance to induce ferroptosis and immunogenic cell death, synergistically activating STING pathway to facilitating the transition of tumors from a “cold” to a “hot” immunophenotype. In this study, hyaluronic acid-functionalized hollow manganese dioxide nanoparticles loading β-lapachone (hMnL), engineered for targeted chemo-immunotherapy is constructed. In vitro investigations reveal that hMnL induces robust reactive oxygen species (ROS) generation, triggering ferroptosis and immunogenic cell death. Concurrently, Mn 2+ ions released from hMnL in response to the acidic tumor microenvironment activate the STING pathway, fostering dendritic cell (DC) maturation and M1 macrophage polarization. Activation of the ferroptosis and immune-related pathways was indicated by transcriptome sequencing, which identified significantly differentially expressed genes (e.g., Fth1 , Hmox1 , Calr ). In vivo , hMnL exhibits superior tumor-targeting efficacy and sustained intratumoral retention, culminating in potent tumor growth suppression. Furthermore, hMnL activates STING pathway in tumor, leading to enhanced CD8 + T cell infiltration, and a marked reduction in regulatory T cell (Treg) populations. Additionally, hMnL also shows good immunoprotective effects and long-term biosafety. These findings establish hMnL as a promising therapeutic platform that integrates targeted chemotherapy with immune modulation, offering a potent strategy to overcome immunosuppression and improve clinical outcomes in cancer.