Metal-based nanodrugs for cancer immunotherapy: smart nanosystems, immunomodulatory mechanisms, and translational perspectives

Abstract

The clinical benefits of cancer immunotherapy are primarily limited by low response rates and an immunosuppressive tumor microenvironment (TME). Metal elements such as iron, manganese, copper, and zinc, as essential micronutrients for the body, play a key regulatory role in the development and effector functions of immune cells, giving rise to the interdisciplinary field of metalloimmunology. However, the poor tumor-targeting ability of free metal ions, their high systemic toxicity, and rapid in vivo metabolism severely hinder their clinical translation. This review systematically summarizes research progress on metal nanomedicines as smart delivery systems in tumor immunotherapy, outlining design paradigms for nanoplatforms from an engineering perspective, covering microenvironment-responsive release, active targeting strategies, and multifunctional integration concepts. It elucidates the molecular mechanisms by which metal ions regulate antitumor immunity by inducing immunogenic cell death (ICD), activating the stimulator of interferon genes (STING) signaling pathway, and reshaping the metabolic microenvironment, and explores synergistic strategies combining metal nanomedicines with immune checkpoint blockade (ICB), photothermal therapy (PTT), or photodynamic therapy (PDT). Unlike previous reviews that often focus on either the immunological functions of metal ions or the engineering of nanocarriers in isolation, this review provides an integrated framework that explicitly links metal ion identity, immune pathway engagement, nanoplatform design parameters, and translational barriers. Central to this framework is a mechanism-design matching principle that connects the specific temporal and intensity requirements of each immune activation pathway with tailored material selection and release kinetics. These immune effects are context-dependent and may vary in selected preclinical models. This paper integrates metallobiology, nanomedicine, and tumor immunology to provide a theoretical framework for the precise design of smart metal immunotherapeutics, while identifying key challenges for clinical translation, such as the therapeutic safety window and metal homeostasis compensation mechanisms.