Simulation-guided design of peptide-metal coordination interfaces for next-generation metallo-immunotherapy

Metal ions are crucial regulators of immune signaling, metabolism, and redox homeostasis, but their therapeutic deployment in cancer immunotherapy is limited by systemic toxicity and inadequate spatiotemporal control. Peptide–metal coordination interfaces offer a programmable solution by combining sequence-encoded recognition with tunable coordination chemistry, enabling controlled metal speciation, bioavailability, and stimulus-responsive functions in complex biological environments. This review summarizes how biologically relevant ions, including Mn2+, Zn2+, Cu2+, and Fe2+/Fe3+, modulate innate and adaptive immunity through direct reprogramming of macrophages, dendritic cells, T cells, and natural killer cells, as well as through indirect remodeling of the tumor microenvironment via immunogenic cell death, redox perturbation, hypoxia alleviation, and disruption of immunosuppressive pathways. We discuss essential peptide–metal coordination principles, including natural binding motifs, synthetic coordination primitives, and stimulus-responsive switching mechanisms that enable dynamic regulation of metal–ligand interactions. To accelerate rational discovery, we outline a simulation-guided computational toolbox integrating docking-based prescreening, molecular dynamics, and metadynamics for stability assessment, quantum mechanical/molecular mechanics approaches for electronic-level accuracy, and machine learning workflows for multi-parameter optimization across high-dimensional design spaces. Finally, we survey the application landscape of peptide–metal platforms, from self-assembled ion-reservoir architectures to hybrid systems incorporating lipidic, polymeric, inorganic, or biomimetic carriers for improved pharmacokinetics and combinatorial functionality. Collectively, this perspective connects coordination chemistry with immunoengineering and highlights simulation-guided strategies for designing adaptive metallo-immunotherapeutic nanoplatforms with spatiotemporal precision and translational potential.