Pharmacological effects on anaplerotic pathways alters the metabolic landscape in the tumor microenvironment, causing unpredictable, sustained antitumor immunity.
Pharmacological effects on anaplerotic pathways alters the metabolic landscape in the tumor microenvironment, causing unpredictable, sustained antitumor immunity.
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对回补途径的药理作用改变了肿瘤微环境中的代谢景观，引起不可预测的、持续的抗肿瘤免疫。
DOI：
10.1093/intimm/dxab067
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发表时间：
2022
影响因子：
4.4
通讯作者：
Nishida M
中科院分区：
文献类型：
--
作者：
Udono H ;Nishida M
为了实现持续的抗肿瘤免疫，肿瘤浸润效应CD8 T淋巴细胞（CD8 TILs）必须能够产生包括IFNγ在内的细胞因子，并在抗原识别后在局部肿瘤组织内强劲增殖。CD8 TILs产生IFNγ依赖于糖酵解，而它们的增殖还需要氧化磷酸化（OxPhos）。氧化磷的水平以及氧气的消耗速率取决于线粒体的生物发生，并且需要将代谢前体装载到三羧酸循环中以保持其功能。这被称为骨质疏松。近年来在免疫代谢领域的研究进展表明，药物可影响肿瘤细胞的抗逆转途径，导致肿瘤细胞的代谢下调；相反，这些药物通过上调CD8 TILs中的糖酵解和OxPhos来触发持续的抗肿瘤免疫。药物抑制（和/或激活）对肿瘤细胞和CD8 TILs的逆转作用是不可预测的。仔细剖析潜在的机制可能会带来重要的知识，帮助我们进入癌症免疫治疗的新时代。
To achieve sustained anti-tumor immunity, tumor-infiltrating effector CD8 T lymphocytes (CD8 TILs) must be able to produce cytokines, including IFNγ, and proliferate robustly within the local tumor tissue upon antigen recognition. IFNγ production by CD8 TILs depends on glycolysis, whereas their proliferation additionally requires oxidative phosphorylation (OxPhos). The level of OxPhos, and hence the oxygen consumption rate, depends on mitochondrial biogenesis and requires the loading of metabolic precursors into the tricarboxylic acid cycle to keep it functioning. This is referred to as anaplerosis. Recent advances in the field of immuno-metabolism have shown the impact of pharmacological agents on anaplerotic pathways, resulting in metabolic down-regulation in tumor cells; in contrast, the agents trigger sustained anti-tumor immunity by up-regulating both glycolysis and OxPhos in CD8 TILs. The opposing effects of pharmacological inhibition (and/or activation) on anaplerosis in tumor cells and CD8 TILs are unpredictable. Careful dissection of the underlying mechanism might confer important knowledge, helping us to step into a new era for cancer immunotherapy.
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