Despite the great potential of cuproptosis in tumor therapy, the current cuproptosis-based therapy still suffers from compromised efficiency of immune activation. Pyroptosis, a proinflammatory cell death modality, provides a good opportunity to induce immunogenic cell death (ICD) and promote systemic immune response. However, the synergistic cuproptosis and pyroptosis therapy has not been fully explored. Herein, it is discovered that Cu(II)-based metal-organic framework (MOF) nanoparticles (NPs) can synergistically induce cuproptosis and pyroptosis to evoke ICD for high-efficiency tumor-targeted immunotherapy. Although MOF-199 has been widely used in tumor therapy, the immunogenicity is still unclear. Pluronic F127-modified MOF-199 NPs (MOF-199 NPs) show dual-responsiveness to glutathione (GSH) and hydrogen sulfide (HS). Once entering cancer cells, MOF-199 NPs dissociate in GSH-enriched tumor microenvironment (TME) to release copper ion and induce copper-overload-mediated cuproptosis. Meanwhile, MOF-199 NPs transform to Cu S NPs by in situ sulfidation under HS-enriched colorectal cancer (CRC) TME. Under photothermal and chemodynamic therapy (PTT/CDT) of Cu S NPs, caspase-3 is activated and gasdermin E (GSDME)-related pyroptosis is triggered. The synergistic cuproptosis and pyroptosis have proved the superior antitumor immunity effect in both in vitro and in vivo experiments. This work provides a new strategy to achieve tumor-targeted immunotherapy with high efficiency by simple MOF-199 NPs.