Multi-metal cooperation drives chemoresistance in lung cancer and is reversed by the membrane-permeable chelator MiADMSA.

Abstract

Elevated levels of transition metals are a common feature of solid tumours and are associated with poor clinical outcomes. However, tumour cells are exposed to complex metal mixtures rather than individual ions, and the functional consequences of such multi-metal exposure remain poorly defined. Here, we show that subtoxic combinations of metals cooperate to drive robust chemoresistance in lung cancer cells. This phenotype is not recapitulated by any single metal, demonstrating that resistance arises from coordinated multi-metal activity rather than individual metal effects. We further find that endogenous metal pools contribute to this response, and that metal-induced reactive oxygen species (ROS) are required but not sufficient, indicating that additional metal-dependent signalling mechanisms underpin chemoresistance. Because resistance emerges from collective metal activity, targeting individual metals fails to restore chemosensitivity. We therefore evaluated a pan-metal chelation strategy and identify monoisoamyl dimercaptosuccinic acid (MiADMSA) as a membrane-permeable chelator capable of targeting intracellular metal pools. Using complementary biochemical and cellular approaches, including a fluorinated derivative to track intracellular activity, we demonstrate that MiADMSA acts within cells to reverse metal-induced chemoresistance across multiple lung cancer models. Importantly, MiADMSA suppresses tumour growth in metal-exposed xenografts. Together, these findings identify multi-metal cooperation as a previously underappreciated driver of chemoresistance and establish intracellular pan-metal chelation as a potentially actionable strategy to restore chemotherapy sensitivity.