The emerging cellular metal ions-immune axis in cancer.

Abstract

Cancer immunotherapy is frequently hindered by the immunosuppressive tumor microenvironment. Although metal ions have been viewed as essential nutrients or cytotoxic payloads, emerging evidence reveals that they are potent immune modulators that orchestrate the cancer-immunity cycle. Here, we synthesize how ionic competition dictates immune cell plasticity and metabolic fate. We detail how metal ions regulate cell death pathways and immune signaling cascades, including the cyclic GMP-AMP synthase-stimulator of interferon genes and nuclear factor kappa B pathways, as well as immunological synapse formation and immune cell responses. Finally, we evaluate the clinical potential of targeting the metal ions-immune axis, from metallomic biomarkers, including Zrt-/Irt-like protein transporters and ion channels, to metallo-immunotherapy strategies. This framework provides a mechanistic roadmap for developing combination therapies to overcome immunotherapy resistance and harness the cellular metallome for precision oncology.