Cancer stemness, characterized by the self-renewal and differentiation capabilities of cancer stem cells (CSCs), is a critical determinant of colorectal cancer (CRC) chemo-immunotherapy. Herein, we repurposed copper-coordination driven metal-organic nano-frameworks (Cu-MOFs) to address the chemo-immunotherapy resistance posed by cancer stemness. These repurposed Cu-MOFs were loaded with the chemotherapeutic agent cisplatin (CDDP), resulting in the formation of Cu-MOF@CDDP. The Cu-MOF@CDDP are efficiently internalized by CRC cells via nanoparticle mediated endocytosis, where they release free copper ions (Cu2+) and CDDP in a high-glutathione (GSH) environment. After that, CDDP forms DNA-CDDP adducts that inhibit DNA synthesis and repair, while Cu2+ induces cuproptosis by disrupting mitochondrial metabolism. Moreover, DNA fragments originating from both the nucleus and mitochondria activate the cGAS-STING pathway, thereby initiating antitumor immune responses. Meanwhile, Cu2+ depletes intracellular GSH and induces cuproptosis, leading to the downregulation of stemness-related proteins such as ZEB1 and c-MYC, which enhances the efficacy of chemoimmunotherapy by targeting the critical pathways involved in maintaining stemness. Consequently, our results underscore the substantial promise of Cu-MOFs in overcoming stemness-driven therapeutic resistance, offering a transformative approach to sensitize chemo-immunotherapy.