Background Ferroptosis holds promise as a potential tumor therapy by programming cell death with a hallmark of reactive oxygen species (ROS)-induced lipid peroxidation. However, vigorous energy metabolism may assist tumors to resist oxidative damage and thus weaken the effects of ferroptosis in tumor treatment. Results Herein, a bifunctional antitumor platform was constructed via coordinated interactions between metal ions and nucleotides to synergistically activate ferroptosis and interrupt energy metabolism for tumor therapy. The designed nanoparticles were composed of Fe2+/small interfering RNA (siRNA) as the core and polydopamine as the cloak, which responded to the tumor microenvironment with structural dissociation, thereby permitting tumor-specific Fe2+ and siRNA release. The over-loaded Fe2+ ions in the tumor cells then triggered ferroptosis, with hallmarks of lipid peroxidation and cellular glutathione peroxidase 4 (GPX4) down-regulation. Simultaneously, the released siRNA targeted and down-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in the tumor to inhibit glycolytic pathway, which interfered with tumor energy metabolism and enhanced Fe2+-induced ferroptosis to kill tumor cells. Conclusions This study presents a concise fabrication of a metal ion/nucleotide-based platform to integrate ferroptosis and energy metabolism intervention in one vehicle, thereby providing a promising combination modality for anticancer therapy. Graphical Abstract

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Chemodynamic therapy (CDT) based on Fenton‐like reaction possesses great potential for anticancer therapy with high efficiency and specificity. However, CDT still suffers low therapeutic efficiency due to intratumoral insufficient H2O2 or unfavorable tumor microenvironment. To enhance tumor treatment and in particular prevent tumor recurrence, the combined strategies with CDT are essentially needed. Herein, a nanocomposite based on Mn2+ and cytosine‐phosphate‐guanine oligonucleotides (CpG ODNs) (MnCpGPNCs) is constructed to combine CDT with immunostimulating responses by exploiting Mn2+‐induced CDT and Mn2+/CpG ODNs‐coinduced immunotherapy against mouse colon tumor cells. Specifically, MnCpGPNCs efficiently deliver and sensitively release Mn2+ in tumor cells to trigger Fenton‐like reaction, causing cell apoptosis. Importantly, Mn2+ also promotes the stimulator of interferon genes pathway to increase the production of type I interferons, thus increasing cytotoxic T lymphocyte infiltration, dendritic cell maturation, and proinflammatory cytokine secretion. Furthermore, CpG ODNs serve as immune adjuvant enhanced the antigen presentation and immune‐eliciting potency. The combination of Mn2+‐based CDT with augmented immunotherapy efficiently inhibits the primary/distance tumors and prevents tumorigenesis. Overall, this newly developed metal‐CpG system demonstrates a paradigm to expand chemodynamic agents as immunotherapy boosters to complement current treatments for tumor elimination and prevention.