线粒体代谢重编程驱动肿瘤免疫耐受的机制及干预策略研究进展

Advances in Mechanisms and Therapeutic Strategies of Tumor Immune Tolerance Driven by Mitochondrial Metabolic Reprogramming

摘要

肿瘤细胞通过线粒体代谢重编程，在维系自身恶性增殖的同时，系统重塑肿瘤微环境（tumor microenvironment，TME）生态位，是导致免疫治疗耐受的重要机制。不同于传统能量代谢的单一研究视角，综述系统剖析线粒体作为免疫调节中枢驱动 TME 向免疫抑制表型演变的规律。在此基础上，重点阐释 TME 内营养竞争与代谢物异常累积、线粒体稳态失衡引发的细胞间信号级联，阐明 AMP 活化的蛋白质激酶与哺乳动物雷帕霉素靶蛋白等重要信号通路的交叉调控机制。同时，系统总结靶向线粒体代谢联合免疫治疗的临床转化研究进展，梳理线粒体代谢重塑、免疫微环境紊乱与肿瘤免疫耐药的整体调控关联，为通过代谢干预重塑抗肿瘤免疫应答、开发代谢与免疫联合治疗新方案提供理论依据与研究思路。

Abstract

Tumor cells systematically reshape the ecological niche of tumor microenvironment (TME) through mitochondrial metabolic reprogramming while sustaining their own malignant proliferation, serving as a crucial mechanism driving resistance to immunotherapy. Different from the conventional research perspective focusing merely on energy metabolism, this review systematically analyzes how mitochondria act as an immunoregulatory hub to drive the evolution of the TME toward an immunosuppressive phenotype. On this basis, it mainly illustrates the intercellular signaling cascades induced by nutrient competition, abnormal metabolite accumulation and mitochondrial homeostasis imbalance in the TME, and elucidates the cross-regulatory mechanisms of key signaling pathways including AMP-activated protein kinase and mammalian target of rapamycin. Furthermore, this review systematically summarizes the clinical translational progress of targeted mitochondrial metabolism combined with immunotherapy, clarifying the holistic regulatory relationship among mitochondrial metabolic remodeling, immune microenvironment disorder and tumor immune resistance, aiming to provide theoretical support and innovative insights for reshaping anti-tumor immune responses via metabolic intervention and developing novel combined metabolic and immunotherapeutic strategies.

关键词

线粒体代谢重编程 / 肿瘤微环境 / 免疫治疗耐受

Key words

mitochondrial metabolic reprogramming / tumor microenvironment / immunotherapy resistance

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基金资助

国家自然科学基金资助项目(82541044)