Women with obesity-driven diabetes are predisposed to more aggressive breast cancers. However, patient metabolic status does not fully inform the current standard of care. We previously identified plasma exosomes as functionally critical actors in intercellular communication and drivers of tumor progression. Here, we generated patient-derived organoids (PDOs) from breast tumor resections to model signaling within the tumor microenvironment (TME). Novel techniques and a short (1-week) culture preserved native tumor-infiltrating lymphocytes for the first time in breast tumor PDOs. After 3-day exosome treatment, we measured the impact of exosomal signaling on PDOs via single-cell RNA sequencing. Exosomes derived from Type 2 diabetic patient plasma significantly upregulated pathways associated with epithelial-to-mesenchymal transition, invasiveness, and cancer stemness, compared to non-diabetic exosome controls. Intratumoral heterogeneity and immune evasion increased in the diabetic context, consistent with enhanced tumor aggressiveness and metastatic potential of these PDOs. Our model of systemic metabolic dysregulation and perturbed transcriptional networks enhances understanding of dynamic interactions within the TME in obesity-driven diabetes and offers new insights into novel exosomal communication.