<p>Cancer stemness, sustained by mitochondrial metabolic plasticity, drives immunotherapy resistance in colorectal cancer (CRC). We reengineer zeolitic imidazolate framework-8 (ZIF-8), a zinc-coordination-driven metal-organic framework, from inert nanocarrier to a multifunctional mitochondrial synchronizer that disrupts stemness through tripartite bioenergetic targeting. A hyaluronic acid (HA)-modified nanoarchitecture (HA/ZGA) co-delivers glucose oxidase (GOx) and 5-aminolevulinic acid (5-ALA), leveraging ZIF-8’s intrinsic Zn²⁺ release for dual metabolic blockade: Zn²⁺ inhibits glucose transporters and electron transport chain activity, while GOx depletes glucose to amplify energy stress. Concurrently, 5-ALA enables cristae-confined photodynamic ROS generation, collapsing oxidative phosphorylation and silencing pluripotency regulators. This metabolic triad coordinately eradicates stemness, reverses PD-L1/CD44 co-expression, and triggers cytotoxic T cell infiltration. In translational models, HA/ZGA achieves potent tumor regression, suppresses metastasis, and establishes immunological memory against rechallenge. Our work redefines ZIF-8 as a therapeutic chameleon that dismantles mitochondrial energetics, ablates stemness, and reignites antitumor immunity, exemplifying nanomaterial repurposing to bridge metabolic intervention with immune potentiation.</p> Graphical Abstract <p></p>