Zinc‐Coordination‐Driven Pyroptosis Nano‐Inductor Sensitizes Colorectal Cancer Chemo‐Immunotherapy by Specific Delivery and Cell Stemness Suppression

ABSTRACT Colorectal cancer (CRC) progression and therapeutic resistance are largely driven by the persistence of cancer stem‐like cells (CSCs) and an immunosuppressive tumor microenvironment (TME). Current therapies often fail to address these two factors simultaneously, limiting their clinical efficacy. In this study, we developed a zinc‐coordination‐driven nanoplatform (CS/ZIF‐8@MIT‐ALA, “CNPs”) designed to simultaneously ablate CSCs and polarize the TME toward an immunostimulatory state. This CD44‐targeted nanoassembly was fabricated by loading a mitoxantrone‐5‐aminolevulinic acid (MIT‐ALA) conjugate into a ZIF‐8 framework, subsequently encapsulated with chondroitin sulfate (CS). CNPs exhibited precise pH‐responsive drug release and superior tumor‐targeting capabilities. In vitro, the synergistic release of Zn 2+ and ALA disrupted glucose metabolism and mitochondrial integrity, thereby effectively suppressing CSC‐associated stemness and triggering gasdermin D (GSDMD)‐mediated pyroptosis. In vivo, CNPs effectively inhibited tumor growth and promoted a pronounced “cold‐to‐hot” tumor transition, as evidenced by enhanced immune cell infiltration and activation. Mechanistically, the integration of metabolic reprogramming with pyroptosis induction amplified antitumor immunity and improved chemo‐immunotherapeutic efficacy. These findings identify CNPs as a promising strategy to overcome CSC‐driven resistance and remodel the CRC immune microenvironment.