Department of Radiation Oncology, Montefiorke Medical Center, Bronx, NY, United States.
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Int Rev Cell Mol Biol. 2024;389:67-103. doi: 10.1016/bs.ircmb.2024.07.003. Epub 2024 Aug 22.
Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).
理解免疫细胞代谢表型及其在肿瘤微环境中的可塑性是理解癌症病理和预后的关键。肿瘤微环境（TME）中的不利条件和细胞应激对免疫细胞的细胞功能产生深远影响，从而影响肿瘤进展和免疫反应。AMP:ATP 比率的升高是葡萄糖水平有限的结果，它激活 AMP 激活的蛋白激酶（AMPK），同时抑制雷帕霉素（mTOR）和缺氧诱导因子 1-α（HIF-1α）的活性。AMPK、mTOR 和 HIF-1α 活性之间的复杂平衡定义了 TME 中免疫细胞的代谢表型。代谢表型的这些变化与免疫细胞功能密切相关，在创造有利于肿瘤进展的环境中起着至关重要的作用。营养和氧气供应不足导致免疫细胞发生代谢转变，表现为糖酵解减少和氧化磷酸化（OXPHOS）和脂肪酸氧化（FAO）率增加。在大多数情况下，这种代谢转变伴随着这些免疫细胞效应功能的降低。这种代谢适应促使免疫细胞降低其效应功能，进入静止或免疫抑制状态，从而可能支持肿瘤生长。本文讨论了肿瘤微环境如何改变免疫细胞的代谢，导致其耐受和肿瘤进展，重点讨论了线粒体代谢（OXPHOS 和 FAO）。
