Diabetic exosomes reprogram tumor-T cell crosstalk to promote immune evasion in breast cancer patient-derived organoids 2078

Abstract Description Women with Type 2 diabetes (T2D) face an increased risk of aggressive breast cancers, yet treatment decisions often overlook metabolic status. We identified plasma exosomes as key mediators of intercellular communication driving pro-oncogenic processes, but their effect on immune cells within the tumor microenvironment (TME) remains unclear. We developed a novel method to generate patient-derived organoids (PDOs) from breast tumors, preserving native tumor-infiltrating lymphocytes (TILs) for the first time. Here, we explored the impact of exosomal signaling on these PDOs via single-cell RNA sequencing. Three-day treatment with T2D-derived exosomes resulted in a 13.6-fold expansion of immunosuppressive TILs compared to nondiabetic controls. These TILs were marked by DDIT3, a stress sensor that inhibits T cell function. Ligand-receptor analysis reinforced these findings, with reduced MHC and CXCL signaling. This immune dysfunction may permit micrometastasis survival and undermine immune checkpoint therapies. Tumor-intrinsic analysis revealed a 1.5-fold increase in intratumoral heterogeneity and upregulation of epithelial-to-mesenchymal transition, invasiveness, and cancer stemness, as seen in our previous data, further implicating exosomes in driving tumor aggression. These findings highlight how metabolic dysregulation in T2D alters tumor-immune crosstalk via exosomal signaling, offering new insights into the TME that could inform personalized treatments for this comorbidity. Funding Sources This work was supported by grants from NIH: U01CA182898, U01CA243004 and R01CA222170 to G.V. Denis; 5T32AI007309 (PI: Gummurulu) to C.S. Ennis. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)