Nanomaterial-induced metal ion interference therapy in cancer treatment: From tumor microenvironment reprogramming to...

Harnessing the biochemical properties of essential ions such as Ca²⁺ , Fe²⁺, Cu²⁺, Mn²⁺, and Zn²⁺ to modulate tumor cell fate, metal ion interference therapy (MIIT) has emerged as an innovative approach for cancer treatment. By disrupting intracellular ion homeostasis, MIIT remodels the tumor microenvironment and induces various forms of programmed cell death, such as apoptosis, ferroptosis, cuproptosis, and pyroptosis, thereby enhancing antitumor efficacy. Despite significant progress, challenges remain in understanding the complex interactions between metal ions and cellular metabolism, as well as in developing optimized combination therapies. Herein, we provide a systematic review of the mechanisms and synergistic strategies of MIIT, focusing particularly on its applications in regulating redox balance, alleviating tumor hypoxia, and disrupting metabolic pathways. We also highlight the recent advances in targeting the electron transport chain (ETC) to impair tumor bioenergetics. Furthermore, the synergistic potential of MIIT combined with immunotherapy and other treatment modalities is discussed, alongside a critical evaluation of the translational barriers of MIIT, including off-target toxicity, metabolic clearance, and narrow therapeutic windows. By bridging the gap between molecular pathophysiology and nanomaterial engineering, the development of MIIT represents a promising approach for the development of effective cancer therapy.