Targeting cuproptosis in cancer: From molecular signaling pathways to therapeutic formulations

The development of resistance against classical proapoptotic chemotherapeutics has led to the evaluation of regulated cell death (RCD) pathways as an innovative opportunity for new anticancer strategies. Cuproptosis is a newly identified RCD modality, associated with the intracellular accumulation of copper leading to aggregation of lipoylated mitochondrial proteins, proteotoxic stress, and cell fate. Here, we present the bivalent nature of copper in cancer biology as a vital cofactor that enhances signaling cascades and networks that promote carcinogenic phenotypes such as well-known MAPKs and PI۳K/AKT pathways, but also as a potent cytotoxic molecule upon homeostasis perturbation. Moreover, this review discusses the complex interaction of copper metabolism and tumor microenvironment (TME), highlighting its impact on immune checkpoint (e.g., PD-L۱) expression and the capacity for cuproptosis to trigger an immunogenic cell death fate to promote antitumor immunity. The spectrum of methods developed to target this pathway is emphasized in our review, ranging from small molecule copper ionophores to nanotechnology-based formulations for targeted delivery and stimulous-responsive release. The targeted induction of cuproptosis is clearly a very attractive and mechanistically unique therapeutic strategy, albeit serious tasks must be addressed including systemic toxic side-effect control as well as adaptive resistance. This review offers an integrated view for elucidating and pharmacologically targeting this new axis in cancer management.

کلیدواژه ها:

Copper homeostasis ، Cancer therapy ، signaling pathways ، Tumor Microenvironment ، nanomedicine