Immune activation strategy based on copper-based nanomaterials: A novel approach to synergistic antitumor therapy

Immunotherapy has emerged as a transformative approach in cancer therapeutics, yet its clinical translation remains constrained by significant challenges, including tumor immune evasion mechanisms and suboptimal efficacy of monotherapy, collectively impeding the full realization of its therapeutic potential. With their unique physicochemical properties, tunable enzyme-mimetic activities, and ability to induce cuproptosis, copper-based nanomaterials provide a new solution to overcome these limitations and have become a research focus in the field of targeted antitumor immunotherapy. This review systematically summarizes the research progress of copper-based nanomaterials in tumor immunotherapy, with a focus on discussing their core antitumor immunological mechanisms. These materials trigger immunogenic cell death by inducing cuproptosis and activate the body’s innate and adaptive immune responses through the release of damage-associated molecular patterns, such as calreticulin, high-mobility group box 1, adenosine triphosphate, and mitochondrial DNA. Meanwhile, they remodel the immunosuppressive tumor microenvironment by alleviating tumor hypoxia, scavenging immunosuppressive metabolites, and reducing immunosuppressive cells. On this basis, this review further analyzes the combined therapeutic strategies of copper-based nanomaterials with immune checkpoint blockade, photodynamic therapy, photothermal therapy, sonodynamic therapy, chemotherapy, and radiotherapy. It also elaborates on the specific mechanisms by which various combined regimens enhance antitumor efficacy, such as through synergistically amplifying oxidative stress, strengthening cell death effects, or improving therapeutic targeting. Additionally, this review discusses the current challenges faced by copper-based nanomaterials in clinical translation and points out future development directions. This review aims to provide a theoretical basis and practical guidance for the clinical translation of multifunctional copper-based nanoplatforms. It also offers new insights for the development of tumor immunotherapies based on metal and redox biology, helping to overcome immune tolerance and improve the efficacy of antitumor treatment.