Nanovaccines with ferroptosis, necroptosis and STING-activation for synergistic immunotherapy

Abstract Nanovaccines based on immunogenic cell death (ICD) present a promising strategy in tumor immunotherapy, serving as a bridge connecting tumor cell death to the induction of anti-tumor immunity. However, their efficacy is severely limited by the immunologically silent nature of apoptosis-dependent ICD and the immunosuppressive tumor microenvironment (TME). In this work, we designed a metal‒polyphenol network nanovaccine (SRF@FeShik-cGAMP/HA). Upon reaching the tumor tissue through specific targeting, the nanovaccines disassemble within the tumor cells, releasing the Fenton reaction catalyst ferrous iron (Fe 2+ ), the system Xc- inhibitor sorafenib (SRF), and necroptosis inducer shikonin. Fe 2+ , SRF, and shikonin collectively promote the accumulation of lipid peroxide and amplify ferroptosis by providing an exogenous iron source, inhibiting glutathione biosynthesis, and boosting reactive oxygen species production, respectively. Meanwhile, shikonin induces necroptosis. The combination of ferroptosis and necroptosis overcomes the limitation of tumor immune silencing and triggers a strong ICD. Simultaneously, the immune adjuvant 2’3’-cyclic-GMP-AMP (cGAMP) activates the STING pathway, reversing the immunosuppressive TME and enhancing the anti-tumor immune response mediated by ICD. The synergistic action of ferroptosis, necroptosis, and the STING pathway produces a cascade of antitumor immune responses and establishes long-term immune memory. This nanovaccine demonstrates promising therapeutic effects in primary, orthotopic, and recurrent hepatocellular carcinoma (HCC) models. Collectively, our findings present a cancer immunotherapy strategy that exploits dual ferroptosis and necroptosis induction to trigger ICD, bypassing the limitations of apoptosis-dependent pathways. This strategy coordinates with the STING pathway to achieve potent antitumor immunity, providing a promising paradigm for HCC treatment, and offering a promising and translatable path for clinical development. Graphical abstract