Mitochondrial stress-induced cuproptosis: a metabolic bridge to reprogramming the GBM immune microenvironment

Glioblastoma (GBM) remains the most lethal primary brain malignancy, characterized by profound metabolic heterogeneity and an immunosuppressive tumor immune microenvironment (TIME) that severely limits the efficacy of immune checkpoint blockade. While cuproptosis has recently been defined as a distinct form of regulated cell death driven by copper-induced mitochondrial proteotoxicity, its non-cell-autonomous roles in remodeling the immune landscape remain poorly understood. This review synthesizes emerging evidence to position cuproptosis not merely as a metabolic collapse, but as a potent driver of immunogenic cell death (ICD). We propose a potential "metabolic-immune" signaling axis wherein copper-triggered aggregation of lipoylated TCA cycle enzymes leads to mitochondrial membrane rupture and the subsequent leakage of mitochondrial DNA (mtDNA) into the cytosol. This danger signal is sensed by the cyclic GMP-AMP synthase (cGAS), activating the STING pathway to stimulate type I interferon production. We discuss how this cascade orchestrates a systemic immune response, including the recruitment of cytotoxic CD8 + T cells and the repolarization of tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Furthermore, we highlight the translational potential of copper ionophores and bioengineered nanomedicines as next generation immunomodulators. By integrating copper metabolism with innate immunity, this review provides a strategic roadmap for exploiting mitochondrial stress to reverse immune exclusion and overcome therapy resistance in GBM.