Wang Yulin, Dong Qiutong, Yuan Menghan, Hu Jingxian, Lin Peizhe, Yan Yijing, Wang Yu, Wang Yanyan
Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
Int Immunopharmacol. 2025 Feb 6;147:113892. doi: 10.1016/j.intimp.2024.113892. Epub 2024 Dec 30.
Breast cancer (BC) ranks among the most prevalent malignancies affecting women, with advanced-stage patients facing an increased mortality risk. Myeloid-derived suppressor cells (MDSCs) contribute significantly to poor prognostic outcomes. Research has concentrated predominantly on the immunological mechanisms underlying MDSC functions, but a comprehensive investigation into the metabolic interactions between BC cells and MDSCs is lacking. In a hypoxic tumor microenvironment (TME), BC cells can enhance aerobic-glycolysis rates, upregulate expression of key lipid metabolism enzymes such as cluster of differentiation (CD) 36 and 5-lipoxygenase (5-LOX), accelerate glutamine (Gln) uptake, and elevate extracellular adenosine (eADO) levels, thereby fostering MDSC proliferation and amplifying immune suppression. Concurrently, alterations in the metabolic state of MDSCs also influence BC progression. To ensure adequate proliferative resources, MDSCs upregulate the pentose phosphate pathway and expedite glycolysis for energy supply while increasing the expression of fatty acid transport proteins (FATPs) such as CD36 and fatty acid transporter 2 (FATP2) to maintain intracellular lipid availability, thereby enhancing their adaptability within the TME. Furthermore, MDSCs undermine T-cell anti-tumor efficacy by depleting essential amino acids (AAs), such as arginine (Arg), tryptophan (Trp), and cysteine (Cys), required for T-cell function. This review elucidates how pharmacological agents such as metformin, liver X receptor (LXR) agonists, and 6-diazo-5-oxo-L-norleucine (DON) can augment anti-cancer treatment efficacy by targeting metabolic pathways in MDSCs. We systematically delineate the mechanisms governing interactions between BC cells and MDSCs from a metabolic standpoint while summarizing therapeutic strategies to modulate metabolism within MDSCs. Our review provides a framework for optimizing MDSC applications in BC immunotherapy.
乳腺癌（BC）是影响女性的最常见恶性肿瘤之一，晚期患者面临着更高的死亡风险。髓源性抑制细胞（MDSCs）是导致不良预后的重要因素。此前的研究主要集中在MDSCs功能的免疫机制上，而对于BC细胞与MDSCs之间的代谢相互作用缺乏全面研究。在缺氧的肿瘤微环境（TME）中，BC细胞可以提高有氧糖酵解速率，上调关键脂质代谢酶如分化簇（CD）36和5-脂氧合酶（5-LOX）的表达，加速谷氨酰胺（Gln）摄取，并提高细胞外腺苷（eADO）水平，从而促进MDSCs增殖并增强免疫抑制作用。同时，MDSCs代谢状态的改变也会影响BC的进展。为确保有足够的增殖资源，MDSCs上调磷酸戊糖途径并加快糖酵解以提供能量，同时增加脂肪酸转运蛋白（FATPs）如CD36和脂肪酸转运蛋白2（FATP2）的表达，以维持细胞内脂质供应，从而增强它们在TME中的适应性。此外，MDSCs通过消耗T细胞功能所需的必需氨基酸（AAs），如精氨酸（Arg）、色氨酸（Trp）和半胱氨酸（Cys），来削弱T细胞的抗肿瘤功效。本综述阐明了二甲双胍、肝脏X受体（LXR）激动剂和6-重氮-5-氧代-L-正亮氨酸（DON）等药物如何通过靶向MDSCs中的代谢途径来增强抗癌治疗效果。我们从代谢角度系统地阐述了BC细胞与MDSCs之间相互作用的机制，同时总结了调节MDSCs内代谢的治疗策略。我们的综述为优化MDSCs在BC免疫治疗中的应用提供了一个框架。
