Targeting cuproptosis with nanomaterials for cancer immunotherapy

Cancer immunotherapy has changed the landscape of tumor treatment. However, its efficacy is often limited by low response rates and drug resistance, especially in immunologically cold tumors. The recent discovery of cuproptosis, a distinct form of copper ion induced programmed cell death, has unveiled a promising strategy to surmount these challenges. Cuproptosis instigates immunogenic cell death, activates the cGAS-STING pathway, and remodels the tumor microenvironment, thereby augmenting antitumor immunity. This review systematically examines the molecular mechanisms of cuproptosis, its regulatory pathways, and synergistic interactions with antitumor immunity. To address the complexity of tumor cell copper efflux mechanisms and microenvironmental barriers, nanomaterials have been innovatively employed for cuproptosis regulation through their advantages in precise targeting, intelligent responsiveness, and multifunctional integration. The review highlights cutting-edge design strategies including mesoporous frameworks and biomimetic nanomaterials. Notably, the crosstalk between cuproptosis and other cell death pathways (such as ferroptosis and pyroptosis), along with its synergistic effects with immune checkpoint blockade, provides multidimensional approaches to overcome tumor resistance. The review further explores the translational potential of cuproptosis from fundamental mechanisms to clinical applications. It synthesizes recent advances in copper homeostasis regulation, multi-omics analytical approaches, cell death interactions, artificial intelligence applications, and precision-targeted delivery systems. This comprehensive analysis aims to provide theoretical support for designing stable and efficient cuproptosis-inducing materials and enhancing the therapeutic efficacy of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: This review systematically summarizes the molecular mechanisms and regulatory pathways of cuproptosis and highlights its synergistic effects with anti-tumor immunity, including M1 macrophage polarization, cGAS-STING pathway activation, and alleviation of the immunosuppressive tumor microenvironment. It provides a detailed overview of nanomaterial-based strategies to induce cuproptosis, covering both endogenous and exogenous copper-based approaches. Potential synergistic interactions with other regulated cell death pathways, such as ferroptosis and pyroptosis, as well as immune checkpoint blockade, are discussed. Clinical translation, challenges in future applications, and therapeutic optimization are addressed, integrating mechanistic insights and nanomaterial strategies, providing a reference for future research on cuproptosis in cancer therapy.