Nanocarriers-oridonin as a dual activator of cGAS-STING and ferroptosis in solid tumors

Oridonin, a bioactive diterpenoid derived from Rabdosia rubescens, has emerged as a promising anti-tumor agent with multifaceted roles in promoting tumor cell death and immune modulation. Recent evidence developments highlight its dual capacity to activate ferroptosis, a form of regulated, iron-dependent cell death, and the cGAS-STING pathway. As a fundamental component of host defense, this critical DNA-sensing axis stimulates innate immunity. This review explores the mechanistic interconnection between these two processes, focusing on how Oridonin-induced oxidative stress and DNA damage drive immunogenic ferroptosis and lead to cytosolic DNA accumulation, which in turn triggers STING-mediated interferon responses. Such dual activation remodels the tumor immune microenvironment, enhances dendritic cell activation, and facilitates T cell-mediated tumor clearance. We further discuss the therapeutic potential of Oridonin in combination with ferroptosis inducers, immune checkpoint inhibitors, and STING agonists. Simultaneously, the use of carriers such as liposomes, micelles, and polymer nanoparticles can significantly improve the water solubility of Oridonin, prolong the circulation half-life, and achieve tumor-targeted enrichment through the enhanced permeability and retention (EPR) effect. Nanocarriers offer the ability to co-deliver Oridonin along with synergistic drugs, such as STING agonists and ferroptosis inducers, to ensure synchronized spatiotemporal release and enhance anti-tumor response. Nanocarriers are combined with imaging agents or biomarkers to achieve real-time monitoring of therapeutic response and dose optimization. However, we need to verify the long-term stability, safety, dose effectiveness, and individualized application potential of nanoformulations through large-scale clinical analyses. Nanotechnology has significantly improved the efficacy and safety of Oridonin through multi-dimensional strategies, providing crucial technical support for its clinical application in immunotherapy of solid tumors. A deeper understanding of these synergistic mechanisms provides essential insights into the development of next-generation cancer immunotherapies that leverage Oridonin’s unique pharmacological characteristics. • Oridonin triggers ferroptosis and cGAS-STING to drive anti-tumor immune activation. • Dual-pathway activation reshapes the tumor immune microenvironment and boosts T cell response. • Nanocarriers improve Oridonin's solubility, bioavailability, and tumor-targeted delivery. • Biomarkers and combination timing optimize Oridonin-based immunotherapy strategies. • Oridonin offers a natural scaffold for next-gen anticancer agents with durable immune effects.