Redox Metabolism and Metabolic Vulnerabilities in Diabetes-Driven Pancreatic Cancer: Targeting System Xc^-, mTORC1,...

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a significant risk factor for pancreatic cancer, with both diseases sharing complex metabolic and molecular underpinnings. Insulin resistance, chronic inflammation, and aberrant activation of the KRAS-mTORC1 signaling axis collectively foster a tumor-permissive microenvironment and disrupt glucose regulation. Recent advances have highlighted disulfidptosis, a novel NADPH-depletion and disulfide-accumulation-driven cell death, as a therapeutic vulnerability in KRAS-mutated, cystine-dependent tumors. This process is linked to the metabolic interplay between glutamate/glutamine and cystine/cysteine, intersecting with mTORC1 signaling and GPX4 regulation. Key regulators, including system Xc^-, GPX4, and GLUT, orchestrate the interplay between insulin resistance, redox imbalance, and oncogenic signaling in T2DM-associated pancreatic cancer. High expression of cystine/glutamate antiporters (system Xc^-) promotes cystine accumulation and NADPH depletion, sensitizing tumor cells to disulfidptosis under glucose deprivation. Biomarker-guided precision medicine approaches leverage SLC7A11, GPX4, and p-mTOR expression to identify patient subsets vulnerable to dual metabolic-redox disruption. Emerging therapeutic strategies focus on restricting glucose availability or manipulating antiporters to induce disulfide stress. Integration of metabolic inhibitors with immune checkpoint inhibitors induces immunogenic cell death and overcomes the immunosuppressive pancreatic tumor microenvironment. Targeting these pathways may overcome therapy resistance and improve outcomes in KRAS- or mTOR-driven malignancies. This review synthesizes mechanistic and translational insights into the cyst(e)ine-mTORC1-GPX4 axis, glutaminolysis, biomarker-guided precision medicine, and disulfidptosis, offering a foundation for future therapeutic development in T2DM-associated pancreatic cancer.