Cantharidin-manganese based cocktail nanoplatform Co-activating ferroptosis and STING for enhanced HCC immunotherapy

Hepatocellular carcinoma (HCC) is often identified during its advanced phases, where therapeutic choices are constrained and patient prognosis is generally poor, creating a critical need for innovative treatment approaches. Despite the promise of immunotherapy, its efficacy is frequently constrained by the immunosuppressive tumor microenvironment (TME). To address this, we developed a multifunctional nanoplatform (CTD/MM@BSA) via a facile "one-pot" method, co-delivering the chemotherapeutic agent cantharidin (CTD) and manganese ions (Mn²⁺) using bovine serum albumin (BSA). This platform leverages the synergistic interplay between ferroptosis induction and cGAS-STING pathway activation to remodel the TME. Upon internalization and subsequent release within tumor cells, CTD and Mn²⁺ act synergistically to boost intracellular ROS levels. This elevation promotes the induction of ferroptosis and ICD. The process culminates in the emission of DAMPs, which in turn activate the maturation of dendritic cells. Simultaneously, DNA damage triggered by CTD acts synergistically with the heightened sensitivity of cGAS to DNA in the presence of Mn²⁺, leading to a marked amplification of cGAS-STING pathway activation and the subsequent production of type I interferons. This bidirectional ferroptosis-immunity activation cascade effectively reverses immunosuppression, promoting cytotoxic T-cell responses. It markedly suppresses tumor growth and metastasis while extending the survival of mice. Moreover, when combined with an anti-PD-L1 antibody (aPD-L1), the therapy demonstrates a stronger synergistic anti-tumor effect. This study overcomes the limitations of free CTD (hepatorenal toxicity) and Mn²⁺ (poor tumor accumulation), offering a potent and targeted strategy to remodel the TME and boost anti-tumor immunity for HCC therapy.