A Single‐Metal‐Doped Nanoplatform for Ferroptosis‐Driven cGAS‐STING Pathway Activation in Hepatocellular Carcinoma Immunotherapy

Abstract The cGAS‐STING signaling pathway effectively activates antitumor immune responses and holds promise for overcoming drug resistance in hepatocellular carcinoma (HCC) immunotherapy. However, achieving specific activation of this pathway in HCC remains challenging. Here, it is introduced a single‐metal‐doped nanoplatform, ZMRPF, which leverages ferroptosis‐induced mitochondrial DNA (mtDNA) release to stimulate cGAS‐STING‐mediated immune activation. ZMRPF initiates HCC ferroptosis by inducing high levels of lipid reactive oxygen species, leading to mitochondrial stress and the release of endogenous mtDNA. This mtDNA synergistically activates the cGAS‐STING pathway, enhanced by immunoactivating Mn 2 ⁺ ions released from ZMRPF. Concurrently, the tumor antigens released during ferroptosis amplify the activity of antigen‐presenting cells, creating a cascade that links ferroptosis with innate immunity. This cascade drives a robust systemic antitumor immune response, effectively reversing the immunosuppressive microenvironment of HCC. These results demonstrate the ability of ZMRPF to reshape the immune microenvironment of HCC and offer a promising strategy for next‐generation tumor immunotherapy.