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 Zn²⁺ 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.

Keywords

cell stemness / chemo-immunotherapy / colorectal cancer / pyroptosis / zinc-coordination-driven nanoassembly

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RIGHTS & PERMISSIONS

2026 The Author(s). MedComm – Oncology published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).