Plasma exosomes from individuals with type 2 diabetes reprogram breast tumor and immune dynamics in patient-derived organoids
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Abstract
The interplay between metabolic disorders and cancer aggressiveness has drawn increasing attention in recent years, particularly in breast cancer patients with comorbid type 2 diabetes (T2D). Obesity-driven diabetes predisposes patients to more aggressive malignancies, yet current clinical approaches largely overlook metabolic contributions to the tumor microenvironment (TME). Our previous work highlighted the role of plasma exosomes, pivotal mediators of intercellular communication, in cancer progression, but their specific effects on immune cells within the TME remain unclear.To address this gap, we developed an innovative platform for generating patient-derived organoids (PDOs) from breast tumor resections, uniquely preserving native tumor-infiltrating lymphocytes (TILs) for the first time. This dynamic and customizable system allows in-depth analysis of tumor-immune interactions in vitro. Using this approach, we treated PDOs with exosomes isolated from T2D patient plasma and employed single-cell RNA sequencing to uncover exosome-driven changes in the TME.
Our findings demonstrated that 3-day treatment with T2D-derived exosomes induced a 13.6-fold expansion of dysfunctional TIL populations compared to non-diabetic controls. This shift towards impaired immune activity may facilitate micrometastatic survival and contribute to the limited efficacy of immune checkpoint therapies in cancer patients with comorbid T2D. Furthermore, analysis of tumor-intrinsic pathways revealed a 1.5-fold increase in intratumoral heterogeneity, and approximately 2.3-fold upregulation of epithelial-to-mesenchymal transition, invasiveness, and cancer stemness markers–consistent with heightened tumor aggressiveness and metastatic potential.
These results underscore the profound impact of metabolic dysregulation on tumor-immune crosstalk, implicating exosomal signaling as a previously underappreciated driver of immune evasion and tumor progression in T2D. By providing a robust platform for modeling the TME and elucidating the molecular mechanisms underlying these effects, this work lays the foundation for developing tailored therapeutic strategies that address the unique challenges posed by metabolic comorbidities in breast cancer.
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2025