Metal-organic frameworks for Cuproptosis-based Cancer therapy

Cuproptosis, a recently identified form of regulated cell death, triggers proteotoxic stress through copper-induced aggregation of lipoylated proteins and disruption of iron–sulfur (Fe S) cluster proteins in the tricarboxylic acid cycle, offering a promising avenue to overcome drug resistance. Though several recent reviews have touched upon nanomaterials for cuproptosis, in this review, we provide the first comprehensive analysis that specifically dedicated to leveraging the unique structural tunability of Metal-Organic Frameworks (MOFs) to precisely trigger this pathway. Unlike generic nanocarriers, MOFs offer distinct advantages through their adjustable porosity, high surface area, and versatile functionalization, which can trigger cuproptosis in tumors by rationally engineering to maximize intracellular copper influx, inhibit efflux, or deplete glutathione (GSH) and glucose with high specificity. We highlight how the multifunctionality of MOFs facilitates synergistic combinatorial therapies, integrating cuproptosis with photodynamic, photothermal, chemodynamic, sonodynamic, radiotherapy, and immunotherapies. Beyond merely summarizing existing literature, this review critically evaluates the structure-activity relationships between MOFs physicochemical properties and cuproptosis efficiency. Crucially, we provide a critical discussion on the intrinsic limitations and translational hurdles of MOFs, including issues of aqueous stability, potential metal ion leaching toxicity, in vivo circulation half-life, and tumor-specific targeting accuracy. In a word, this review aims to provide thoughtful insights and a rational design framework for the next generation of MOF-based cuproptosis inducers, ultimately guiding their path toward clinical application. Cuproptosis shows great potential in cancer therapy and overcoming drug resistance. This review systematically summarizes the research progress of cuproptosis-mediated tumor treatment, classifies and discusses from cuproptosis induction mechanisms, MOFs-based cuproptosis strategies, and combinatorial therapeutic modes, highlights recent advances in MOFs-mediated copper delivery and metabolic regulation as well as copper-induced lipoylated protein aggregation and Fe S cluster disruption, addresses key challenges including scalable production, biocompatibility, and tumor-specific targeting, and prospects the future development of clinical translation of MOF-based cuproptosis therapy. • Cuproptosis, a groundbreaking form of programmed cell death reported in Science in 2022, has precipitated a significant paradigm shift in cancer treatment, and guided novel pathways for targeted therapeutic innovation. • MOFs have unique properties, such as their framework structure, nanopores, high surface area, and functionalizability, which used in cuproptosis-based cancer treatment as platforms. • This review systematically summarizes various strategies for triggering cuproptosis for cancer therapy via copper ion influx, copper ion efflux inhibition, or GSH/glucose depletion in cancer by leveraging the unique properties of MOFs, covering developments from 2022 to 2026. • We emphasize the multifunctionality of MOFs induced single and combinatorial cuproptosis-based cancer therapy that synergizes with photodynamic therapy, photothermal therapy, chemodynamic therapy, sonodynamic therapy, immunotherapy, radiotherapy, for enhanced anticancer efficacy and theranostic applications.