Metal Ions Within the Neuro-Immune-Tumor Axis

Metal ions are key regulators of the neuro-immune-tumor axis. Recent studies provide concrete evidence that neuronal Ca²⁺ pulses drive tumor-neuron integration and shape immune signaling. Synaptic Zn²⁺ and ZIP transporters modulate synaptic transmission and tumor growth. Tumor iron accumulation fuels proliferation while creating a clear ferroptosis vulnerability. Copper promotes angiogenesis, lysyl oxidase (LOX)-mediated extracellular matrix (ECM) remodeling and metastasis, and implicates cuproptosis as a therapeutic target. Mn potentiates cyclic GMP-AMP synthase (cGAS)-STING signaling and serves as both an immune adjuvant and manganese-enhanced magnetic resonance imaging (MEMRI) contrast. Besides, Mg and K⁺ regulate kinase/T-cell receptor (TCR) function and tumor-neuron excitability, respectively. Despite these advances, major gaps persist, notably limited spatial and temporal mapping of labile metal pools, a paucity of cell-type-specific causal perturbations, and underdeveloped tumor-targeted metal-modulating therapies with proven safety. We therefore propose a focused research agenda: integrate spatial metallomics with single-cell multiomics, deploy metal-sensitive longitudinal imaging, apply conditional genetic and chemogenetic perturbations and organotypic models to dissect neuro-immune cross-talk, and implement preclinical pipelines emphasizing tumor-selective delivery and comprehensive safety testing.