肿瘤微环境（TME）的代谢异质性是癌症的一个标志和抗癌治疗的一个重要障碍。癌细胞在营养条件恶劣的环境中表现出利用替代碳源，尤其是核苷酸的多样能力。然而，嘌呤（尤其是核苷）在调节线粒体代谢以缓冲营养不良方面的作用尚未被很好定义。在这里，我们发现诱导5'-核苷酸酶，胞浆Ⅱ（NT5C2）基因表达可以促进核苷的积累，并在营养贫乏地区维持癌细胞的存活。核苷的升高进一步通过增加转录因子SP1的水平诱导Rag GTP酶蛋白和mTORC1信号通路在饥饿的肿瘤中的丰度。此外，核苷的补充还刺激新生TCA循环酶的合成，包括柠檬酸合成酶（CS）和顺丁烯二酸酶1（ACO1），以进一步增强葡萄糖饥饿条件下乳腺癌细胞的氧化磷酸化作用，导致异柠檬酸的积累。抑制CS的活性或敲低ACO1会阻断核苷对饥饿情况下癌细胞存活的拯救效应。综上所述，我们的发现突出了核苷在连接线粒体呼吸和缓冲饥饿方面的重要信号作用，不仅仅作为TME中的直接能源载体或遗传密码的构建模块，为通过靶向核苷代谢进行未来的癌症治疗提供了新的视角。© 2023. 作者及作者团队.

Metabolic heterogeneity of tumor microenvironment (TME) is a hallmark of cancer and a big barrier to cancer treatment. Cancer cells display diverse capacities to utilize alternative carbon sources, including nucleotides, under poor nutrient circumstances. However, whether and how purine, especially inosine, regulates mitochondrial metabolism to buffer nutrient starvation has not been well-defined yet. Here, we identify the induction of 5'-nucleotidase, cytosolic II (NT5C2) gene expression promotes inosine accumulation and maintains cancer cell survival in the nutrient-poor region. Inosine elevation further induces Rag GTPases abundance and mTORC1 signaling pathway by enhancing transcription factor SP1 level in the starved tumor. Besides, inosine supplementary stimulates the synthesis of nascent TCA cycle enzymes, including citrate synthesis (CS) and aconitase 1 (ACO1), to further enhance oxidative phosphorylation of breast cancer cells under glucose starvation, leading to the accumulation of iso-citric acid. Inhibition of the CS activity or knockdown of ACO1 blocks the rescue effect of inosine on cancer survival under starvation. Collectively, our finding highlights the vital signal role of inosine linking mitochondrial respiration and buffering starvation, beyond serving as direct energy carriers or building blocks for genetic code in TME, shedding light on future cancer treatment by targeting inosine metabolism.© 2023. The Author(s).