Ennis Christina S, Seen Michael, Chen Andrew, Kang Heejoo, Ilinski Adrian, Mahdaviani Kiana, Ko Naomi Y, Monti Stefano, Denis Gerald V
Cancer Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
Department of Medicine, Computational Biomedicine Section, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
Commun Biol. 2025 Aug 26;8(1):1276. doi: 10.1038/s42003-025-08663-y.
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.
肥胖驱动的2型糖尿病（T2D）女性面临更差的乳腺癌预后，然而代谢状况并不能完全指导当前的护理标准。我们之前确定血浆外泌体是肿瘤进展的关键驱动因素；然而，它们对肿瘤微环境（TME）中免疫细胞的影响仍不清楚。使用一种新型的患者来源类器官（PDO）系统来保留天然肿瘤浸润淋巴细胞（TILs），我们发现与非糖尿病对照组相比，T2D血浆外泌体可使免疫抑制性TILs扩增13.6倍。这种免疫功能障碍可能会促进微转移存活以及对检查点阻断的抗性，这是T2D癌症患者中一个已知的问题。肿瘤内在分析显示肿瘤内异质性增加了1.5倍，侵袭性信号网络上调了2.3倍。这些发现揭示了T2D相关的代谢失调如何通过先前未被充分认识的外泌体信号改变肿瘤-免疫串扰，损害抗肿瘤免疫力并加速进展。了解这些动态变化可为这一高风险、未得到充分治疗的患者群体提供量身定制的治疗方法。
