Abstract
Women with obesity-driven type 2 diabetes (T2D) face worse breast cancer outcomes, yet metabolic status does not fully inform current standards of care. We previously identified plasma exosomes as key drivers of tumor progression; however, their effect on immune cells within the tumor microenvironment (TME) remains unclear. Using a novel patient-derived organoid (PDO) system that preserves native tumor-infiltrating lymphocytes (TILs), we show that T2D plasma exosomes induce a 13.6-fold expansion of immunosuppressive TILs relative to nondiabetic controls. This immune dysfunction may promote micrometastatic survival and resistance to checkpoint blockade, a known issue in T2D cancer patients. Tumor-intrinsic analysis revealed a 1.5-fold increase in intratumoral heterogeneity and 2.3-fold upregulation of aggressive signaling networks. These findings reveal how T2D-associated metabolic dysregulation alters tumor-immune crosstalk through previously underappreciated exosomal signaling, impairing antitumor immunity and accelerating progression. Understanding these dynamics could inform tailored therapies for this high-risk, underserved patient population.