Metal homeostasis as a therapeutic lever: advancing metalloimmunology to remodel the tumor microenvironment and enhance cancer immunotherapy.

Targeting the dysregulation of essential metal homeostasis represents a rapidly evolving frontier in cancer immunotherapy. The tumor microenvironment (TME) is a complex immunosuppressive ecosystem comprising tumor cells, immune cells, stromal components, extracellular matrix, and diverse cytokines/chemokines, characterized by hypoxia, acidosis, elevated redox stress, and metabolic dysregulation that drive tumor progression and immunotherapy resistance. Crucially, dysregulated homeostasis of essential metals (e.g., Cu, Fe, Zn, Mg, Mn, Ca, Cr, Na, K) pervades the TME, directly promoting tumorigenesis through oncogenic pathway activation and aberrant energy metabolism while facilitating immune evasion, amplifying immunosuppression, and undermining cancer immunotherapies. In response, recent strategies have focused on leveraging metalloimmunology to reprogram the TME via: (1) activation of innate/adaptive immunity, (2) disruption of tumor metabolism, (3) induction of programmed cell death, and (4) triggering of immunogenic cell death (ICD). These approaches synergize with existing immunotherapies to enhance efficacy, aided by nanotechnology-enabled precision delivery of metal-based agents. In conclusion, by mastering the intricate interplay between metal ions and the immunosuppressive TME, these strategies hold immense potential to remodel the TME, reinvigorate anti-tumor immunity, and ultimately enhance the efficacy of next-generation cancer immunotherapies. This review presents metalloimmunology as an integrative paradigm connecting metal biology, tumor immunology, and nanotechnology, providing a transformative outlook for immunotherapy.